More MS news articles for Sep 2001

NMSS: New Research - Recently Funded Projects - Fall 2001

Summaries of 60 New Research Projects

http://www.nationalmssociety.org/pdf/research/NewResearch.pdf

September 14, 2001

The National Multiple Sclerosis Society has just committed $18 million to support 60 new MS research projects with terms running from one to five years. These projects, out of 150 proposals reviewed by our volunteer panels of scientific advisors, were found to be of the highest scientific merit and significance in the fight against MS.

Thanks to generous research-restricted gifts and Research Honor Roll gifts from National MS Society chapters, we were able to make commitments to find funding support for ALL of these projects approved by our advisors. However, when research commitments are made, the money is not in hand to meet them: The Society has over $40 million in current- and future-year commitments to meet. Money must be raised each year to fulfill them. Contributions to the Society to help support these projects are essential to helping us meet our financial obligations.

The 60 new projects are part of a research program that spent nearly $30 million this year alone to advance MS research, including funding over 300 new and ongoing investigations in the U.S. and abroad. Since our founding in 1946, the Society has invested $320 million to support basic and clinical research aimed at finding a cure for MS.

Following are brief summaries of the new projects, grouped according to major avenues of MS investigation. In addition, new one-year, “high-risk” projects awarded over the last six months through the Pilot Research Program are listed on page 12-13.

The new projects fall into six categories:

TREATMENT/REHABILITATION

Seeking Better Therapies

Ultimately, the goal of the biomedical research program of the National MS Society is to develop therapies (both medications and rehabilitation programs) that will combat MS. The Society supports clinical treatment and rehabilitation trials in a number of ways:

Moreover, the Society’s sponsorship of basic
and clinical research lays the foundation
upon which most clinical trials are based.

Following are summaries of seven new
clinical studies that investigate experimental
methods of diagnosis and treatment. Four of
these new grantees are Sylvia Lawry Physician
Fellows, who are receiving training and
hands-on experience in designing and conducting
clinical trials.
 

Carlo Antozzi, MD
National Neurological Institute Carlo Besta Milan, ITALY
Award: Research Grant
Term: 9/30/01 - 9/30/03
Funding: $177,100

“IgG immunoadsorption in steroid-resistant relapses of MS: a pilot study”

A small clinical study of a novel immune-protein cleansing treatment for people with MS who do not respond to steroid therapy for acute attacks.

The main therapy to shorten acute attacks of relapsing-remitting MS is high doses of oral, or more often, intravenous steroids. For unknown reasons, some people do not respond to this therapy. Carlo Antozzi, MD, is conducting a small clinical trial of a new therapy that targets a group of immune proteins that have been implicated in these acute MS relapses. Dr. Antozzi’s technique involves passing the blood through a special filter that traps specific immune proteins called immunoglobulins (IgG), specific antibodies which some research suggests play a role in the nervous tissue destruction that is the hallmark of MS.

Ten people with relapsing-remitting MS experiencing acute attacks are undergoing this procedure. Dr. Antozzi is assessing symptom severity and various immunological markers of the disease. If results are encouraging, this small-scale trial could lead to a larger trial of this potential therapy for people whose MS attacks are unresponsive to steroid therapy.
 

Toni M. Bauman, MD
Dartmouth Medical School
Lebanon, NH
Area: Central New England Chapter
Award: Sylvia Lawry Physician Fellowship
Term: 10/1/01 - 9/30/04
Funding: $120,000

Sylvia Lawry Physician Fellowship

Receiving training on the proper ways to conduct clinical treatment trials in MS.

During the course of her physician fellowship, Toni M. Bauman, MD, will be engaged in helping to design and conduct clinical trials in persons with MS under the experienced eyes of top MS experts at the Dartmouth-Hitchcock Medical Center.

Dr. Bauman is also focusing on fatigue and depression, which are common and troubling symptoms of MS, and the possible connection between immune-system activity and these symptoms. To do so, she is studying individuals currently enrolled in a clinical trial to evaluate the effectiveness of a drug that targets immune molecules thought to help initiate the MS-causing immune response.

She is correlating levels of immune messenger chemicals and cells with depression and fatigue, and determining whether treatment with the study drug alters these immune factors. She is then exploring whether and how these changes affect levels of fatigue and depression.

In addition to training Dr. Bauman to carry on the crucial work of conducting clinical trials in MS, this project may provide important information about biological underpinnings of fatigue and depression in MS.
 

Ruth Ann Marrie, MD
Cleveland Clinic Foundation
Cleveland, OH
Area: Northeast Ohio Chapter
Award: Sylvia Lawry Physician Fellowship
Term: 7/1/01 - 6/30/04
Funding: $120,500

Sylvia Lawry Physician Fellowship

Receiving training on the proper ways to conduct clinical treatment trials in MS.

During her three-year physician fellowship, Ruth Ann Marrie, MD, is working under the mentorship of experienced MS experts at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. In addition to developing expertise in MS clinical trials, Dr. Marrie is also exploring cognitive impairment in MS.

Neuropsychologists have developed a variety of tests to measure the effects of disease on a person’s quality of life, and such “instruments” are increasingly employed in clinical trials to determine whether a drug under study improves the quality of day to day living. One instrument used in MS is called the MSQLI, which requires patients to respond to various questions. Dr. Marrie is testing whether cognitive impairment in MS alters, in unseen ways, the validity of people’s responses to the MSQLI. If she finds that cognitive impairment interferes with getting a true measurement, it may be necessary to alter the instrument or how it is administered.
 

Virgil G. Mathiowetz, PhD
University of Minnesota
Minneapolis, MN
Area: Minnesota Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $268,048

Effects of an energy conservation course for persons with multiple sclerosis

Can strategies to save energy and ward off fatigue improve quality of life in people with MS?

Fatigue is one of the most common symptoms of MS, occurring in about 80% of those with the disease. “Energy conservation strategies” – such as effort-saving devices, eliminating or delegating tiring tasks, and including rest periods into every day – are often recommended to people with MS by occupational therapists. Virgil G. Mathiowetz, PhD, is trying to determine if these strategies really help by evaluating a six-week course that teaches energy conservation.

With the help of the Society’s Minnesota and Greater Illinois chapters, Dr. Mathiowetz is recruiting 160 people to participate. Scales that measure fatigue will be administered before and after the course to determine any changes. Participants will be followed for one year after completing the course so researchers can determine how long any effects of the course last. The study is also testing whether participants fully understand and use the lessons, and whether this comprehension helps them combat fatigue.

This study will help identify simple energy-saving strategies to help people with MS manage fatigue.
 

Michael K. Racke, MD
Univ. of Texas Southwestern Medical School
Dallas, TX
Area: Lone Star Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $361,039

Immunologic evaluation of therapeutic strategies in MS

Characterizing the immune responses of people with MS to therapies that involve intense immune-system suppression.

By definition, individuals with secondary-progressive MS begin with a relapsing-remitting course of disease which over the years shifts to a condition of persistent neurologic dysfunction and a steady worsening of symptoms. Only recently has there been an immune-suppressing drug, Novantrone (mitoxantrone), approved for its treatment.

A more invasive treatment is the experimental procedure of “replacing” the immune system by removing bone marrow-type stem cells from an individual’s blood, killing his or her circulating immune cells, and then returning the stem cells that eventually reconstitute the immune-system cells. This procedure is called autologous stem cell therapy (SCT).

Michael K. Racke, MD, is using an NIH-funded clinical trial currently underway, comparing the effectiveness of Novantrone and SCT in secondary-progressive MS, to study the impact of these treatments on immune function. He is collecting blood and spinal fluid from ten of the study participants before and after therapy to monitor how immune cell numbers and activity are affected by the two treatments. He is especially focusing on the activity of immune T cells and B cells and their by-products, and is also comparing his findings with those from individuals with other forms of MS who are not enrolled in the trial.

These studies will provide important information
about the immune-system attack in
secondary-progressive MS and how these
two therapies may work. This may suggest
ways to improve outcomes for people with
severe forms of MS.
 

Albrecht Neiss, PhD
Technical University of Munich
Munich, Germany
Award: Research Grant
Term: 7/1/01 - 6/30/05
Funding: $800,000

Sylvia Lawry Centre for Multiple Sclerosis Research

Collecting and analyzing
MRI and clinical data from MS drug trials
to increase knowledge of the natural
history of the disease and to speed the development
of new treatments.

The Sylvia Lawry Centre is an innovative international collaborative effort to maximize data available from natural history studies and clinical trials of MS therapies.

This multi-million dollar center for MS research was set up under the auspices of the Multiple Sclerosis International Federation (MSIF), and is named for the late founder of the National MS Society and the MSIF.

Dr. Neiss and a team of top statisticians and biometricians, guided by an oversight committee of MS, are collecting data from all major natural history studies and clinical trials of treatments for MS. The team will use advanced mathematical and computerized methods to analyze this information and make data available for analysis to investigators interested in studying MS.

One of the first efforts of the center will involve analyzing placebo groups from clinical trials – groups of people that take an inactive substance, for comparison with the people actually taking the drug under study. Dr. Neiss and colleagues hope to create “virtual” placebo groups, that is, statistics that describe the natural course of MS. Clinical researchers could then use these statistics in the evaluation of new therapies. This resource could help to develop new treatments for MS more speedily, efficiently and cost-effectively, while avoiding the need for people with MS to take inactive substances during clinical trials.

Ultimately, the Sylvia Lawry Centre may provide data to create “virtual” placebo groups for MS clinical trials.

Mark J. Tullman, MD
Mount Sinai Medical Center
New York, NY
Area: New York City Chapter
Award: Sylvia Lawry Physician Fellowship
Term: 7/1/01 - 6/30/03
Funding: $80,000
Paid in part by the NMSS New York City Chapter through the Martin S. Davis Research Fellowship Endowment

Sylvia Lawry Physician Fellowship

Receiving
training on the proper ways to
conduct clinical treatment trials in MS.

Mark J. Tullman, MD, is a young physician undergoing a comprehensive training program in multiple sclerosis at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai, one of the country’s major MS clinical trial groups.

He is learning all aspects of designing and conducting small- and large-scale clinical trials in people with MS. This work includes hands-on experience with patients who are or will be enrolled in clinical trials of intravenous immunoglobulins, oral versus intravenous steroids to treat acute attacks, and combinations of Novantrone with other disease-modifying agents. Dr. Tullman is especially focusing on their overall effects on quality of life. He is also doing coursework in biostatistics, epidemiology, health policy and outcomes, ethics, and data management, and taking advantage of the top-notch basic research on myelin biology at Mt. Sinai to develop a better appreciation of laboratory techniques and the effort it takes to translate neuroscience research into MS therapies.
 

Marina E. Zvartau-Hind, MD
Wayne State University
Detroit, MI
Area: Michigan Chapter
Award: Sylvia Lawry Physician Fellowship
Term: 7/1/01 - 6/30/04
Funding: $120,000

Sylvia Lawry Physician Fellowship

Receiving training on the proper ways to conduct clinical treatment trials in MS.

Marina E. Zvartau-Hind, MD, is doing her physician fellowship at a Multiple Sclerosis Center whose investigators have been engaged in multiple clinical trials of medications used for disease modification and symptomatic treatment of MS. She is participating in two landmark clinical trials:

Dr. Zvartau-Hind is also engaged in learning how clinical trials are designed properly, and being exposed to all aspects of a busy MS center, including the close integration of clinical care, research, and state-of-the-art imaging techniques in people with MS.

Coursework will complement her hands-on experience. Ultimately, Dr. Zvartau-Hind will be an independent investigator ready to design and conduct clinical trials of the next generation of better treatments for MS.
 

EPIDEMIOLOGY

Who Gets MS?

Epidemiologists evaluate disease patterns among people with a certain disease, taking into account variations in geography, demographics, socioeconomic status, genetics, and exposure to infectious and toxic agents. They study the relationships between these factors, as well as patterns of migration, that may be related to areas with high or low rates of MS.

By exploring who gets MS, we can begin to understand why this disease appears more frequently in certain populations, and why some people may be protected. Epidemiological studies ultimately seek to discover the cause of MS, and may also serve as the basis for developing future treatments.
 

Miguel Hernan, MD, DrPH
Harvard School of Public Health
Boston, MA
Area: Central New England Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $325,358

Risk factors and incidence of MS in a population-based follow-up study

Asking whether studying medical data on a large group of people over time can reveal possible risk factors contributing to the development of MS.

Identifying the cause of chronic diseases such as MS is complex, and epidemiology plays a crucial role in this search. By studying large numbers of people with MS, epidemiologists hope to make major headway in identifying risk factors for the disease.

Miguel Hernan, MD, DrPH, is studying just such a population – more than 4 million people who are registered in the United Kingdom’s General Practice Research Database. His team includes investigators who have used this tool, which tracks medical data of individuals over time, to unearth valuable information that might be informative about the development of a whole host of diseases.

Dr. Hernan is searching the database for individuals who have MS, and is gathering such general information as the age of diagnosis and sex, as well as more specific information that might reveal possible MS risk factors, such as: use of oral contraceptives and other sex hormones, smoking, hepatitis B vaccination, and viral infection. The team also is studying the relationship between MS and other conditions, such as allergy and diabetes. They are attempting to analyze risk factors for different clinical courses of MS (e.g., relapsing-remitting, secondary-progressive) separately.

This study is one of the largest ever conducted on risk factors for MS, and may lead to a greater understanding of how this disease develops.
 

HEALTH CARE DELIVERY AND POLICY RESEARCH

Improving Quality of Life

MS can have profound effects beyond medical problems, including impacts on family life, career, standard of living and general quality of life. MS also involves special concerns for medical care: Do individuals with MS have access to quality health care and health care insurance? Access to specialists?

Investigators working under the auspices of the National MS Society’s Health Care Delivery and Policy Research Program study such issues, providing data that can serve as the basis for influencing public policy, and offering people with MS and their families practical ways for improving the quality of their lives.

With the help of its volunteer Health Care Delivery and Policy Research Advisory Committee, the Society establishes priority areas each year and releases a request for proposals from investigators in the field. The priority areas for 2001 focus on: long-term care studies in MS; and incentives and disincentives for work and disability among persons with MS. The following two new projects responding to those priorities were recently awarded.
 

Robert J. Buchanan, PhD
Texas A&M University
College Station, TX
Area: Lone Star Chapter
Award: Health Care Delivery & Policy Re-search
Contract
Term: 7/1/01 - 6/30/04
Funding: $446,257

The long-term care needs of people with multiple sclerosis

Exploring the long-term care needs of people with MS and the services they receive in care facilities.

Approximately one quarter of people with MS will need long-term care at some point during their illness. Robert Buchanan, PhD, is examining long-term care provided for people with MS, focusing particularly on how care needs change as disability levels increase.

Several long-term care options are available, including nursing homes and an array of home- and community-based support services.

Dr. Buchanan is profiling nursing home residents with MS and analyzing the care they receive to determine the impact of specific services, such as physical therapy, counseling, drug therapies and group therapies, on their physical and mental health. He is also surveying informal caregivers who provide in-home and community-based care to learn about the services they offer and the barriers that exist to providing this care.

Identifying nursing home characteristics associated with improved quality of life and learning about the impact of formal and informal long-term care will clarify the long-term care needs of people with MS.
 

Phillip D. Rumrill, PhD, CRC
Kent State University
Kent, OH
Area: Northeast Ohio Chapter
Award: Health Care Delivery & Policy Research
Contract
Term: 7/1/01 - 6/30/03
Funding: $437,790

MS employment project

Assessing the employment concerns and needs of people with MS using a national survey.

Given the broad spectrum of symptoms that can accompany MS, the uncertainty of its course, and the profound impact that it makes on every aspect of life, employment looms large as a concern for people with MS. Added to that is the fact that MS often strikes at an age when career development is most critical.

For that reason, Phillip D. Rumrill, PhD, CRC, is seeking to acquire an in-depth understanding of the incentives and disincentives for working among people with MS from their own perspectives. He also is assessing the impact of the Americans with Disabilities Act (ADA) on employment experiences of people with MS, and evaluating the effects of an employment assistance project.

Dr. Rumrill’s findings will aid in the development of vital programs for people with MS who face employment problems.

MEASURING DISEASE ACTIVITY

Tracking the Course of MS

Multiple sclerosis can vary greatly in its symptoms and course. Although we know a great deal about the damage that occurs to tissue in the brain and spinal cord, we do not know enough about how this damage creates the symptoms of MS, and why these symptoms vary. Furthermore, no laboratory or clinical test can predict the course of this disease. Research in this category seeks to fill gaps in our knowledge about the course of MS and factors that may influence that course.

The Society is currently supporting 10 research projects on measuring disease activity, including the following two new projects.

Both are utilizing MRI technology as a window on the disease process.
 

Nancy L. Sicotte, MD
University of California at Los Angeles
Los Angeles, CA
Area: Southern California Chapter
Award: Harry Weaver Neuroscience Award
Term: 7/1/01 - 6/30/06
Funding: $512,867

The onset of progressive MS: structural and functional determinants

Using brain imaging as a way to observe the process by which relapsing-remitting MS becomes a progressive disease.

People newly diagnosed with MS most often have a relapsing-remitting (RR) form of the disease, in which acute attacks alternate with complete or partial remissions. However, many of those with RR MS eventually develop secondary-progressive (SP) MS, characterized by a steady decline in neurological function with or without acute attacks.

It is still not known why or how the transition from RR MS to SP MS occurs, or what pathological changes accompany this transition.

Nancy Sicotte, MD, is conducting a study of 40 people with RR MS who show early signs of secondary-progressive disease to uncover the subtle changes that take place in the brain during this transition. She is using new magnetic resonance imaging (MRI) techniques that detect structural and functional changes in specific brain pathways over time.

Combining structural and functional assessments of the brain should yield important insights into the cause of the transition to SP MS, and may help identify markers of disease progression that could lead to earlier diagnosis and more effective treatments.
 

Lael A. Stone, MD
Cleveland Clinic Foundation
Cleveland, OH
Area: Northeast Ohio Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $375,459

The predictive value of MRI in multiple sclerosis

Determining whether specific methods of MRI can predict the onset of disability in people with MS.

For most people newly diagnosed with MS, a key question is, “What will happen within the next 5 to 10 years?” Because the disease is unpredictable, this is currently impossible to answer. That is where MRI, or magnetic resonance imaging, may come in. MRI is one of the most widely available tools to assess disease activity in MS – especially important because recent evidence suggests that destructive processes are taking place in the earliest stages of MS, and may even precede clinical signs and symptoms.

Thus, MRI may pick up signs of disease long before disability becomes evident.

To explore this idea, Lael A. Stone, MD, is investigating a unique group of people with MS. Followed since 1990 by investigators at the National Institute for Neurological Diseases and Stroke (NINDS, where Dr. Stone was trained), these individuals had baseline MRI examinations 5 to 10 years ago and have been followed regularly. Dr. Stone is now evaluating those MRI scans to see if earlier MRI findings were predictive of individuals’ current disability status. New com-puter-aided analyses will track how disability relates to MRI abnormalities.

If results of this study demonstrate that early MRIs could predict later development of disability, this could significantly affect clinical practice, directing aggressive therapy for people at high risk of disability and sparing those likely to do well.
 

TARGETED RESEARCH GENETICS

Understanding Susceptibility

While MS is not directly inherited, we know that multiple genes – out of an estimated 30,000 needed to make and maintain the human body – likely work in concert with unidentified infections or environmental triggering factor to influence whether a person develops MS.

The National MS Society has been supporting a major genetics initiative since 1991. This entails collecting blood samples, from which genetic material is derived, from families in which more than one member has MS. In addition to this approach, Society-funded investigators are:

Others are searching for genetic clues to why some individuals respond to specific therapies and others do not – the emerging field of “pharmacogenetics.”

Researchers now have clues to the locations of several genes that may contribute to susceptibility to MS, but no single gene has yet been identified. Knowing the identity of these genes will bring vital clues to the actual cause of MS and ways to treat or even prevent it.

The Society is currently funding nine major projects in the targeted area of genetic susceptibility, including the following two new projects.
 

Sergio E. Baranzini, PhD
University of California at San Francisco
San Francisco, CA
Area: Northern California Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/03
Funding: $92,276

Genetic networks and the response of interferon-beta in multiple sclerosis

Analyzing the genes involved in the responsiveness of people with MS to interferon beta therapy.

One of the most significant developments for people with MS has been the introduction of interferon betas for relapsing forms of the disease. But not everyone with MS responds to interferons. That leaves neurologists with a dilemma regarding the appropriate candidates for treatment.

To help determine who is most likely to benefit from interferon therapy, Sergio E. Baranzini, PhD, is conducting a comprehensive study intended to reveal those genes in the immune system that “turn on” and “turn off” in response to interferon, and whether this may serve as a genetic basis for determining who does and does not respond to treatment. He has access to detailed clinical information and genetic material from a study of 200 people with relapsing-remitting MS treated with interferon beta, and is analyzing these data using advanced statistical techniques and software programs.

In addition to providing new information about how interferon beta works, this project may ultimately help health-care providers to optimize the value of treatment options available for people with MS.
 

John Carling Roder, PhD
Samuel Lunenfeld Research Institute
Toronto, CANADA
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $407,622

A forward genetic screen for MS susceptibility genes in animal models

Identifying genetic mutations that cause neurologic disabilities in mice, for clues to genes involved in susceptibility to human MS.

John Carling Roder, PhD, is launching an ambitious project whose goal is to identify mice with genes – the coded instructions that control every aspect of the body’s functions – that cause MS-like neurological symptoms. Mice are being exposed to a chemical that causes genetic mutations, or mistakes, in genes that control neurological functions. In offspring that demonstrate clinical signs of MS, such as loss of motor strength or tremor, Dr. Roder is then identifying the genetic mutations responsible for these defects. With this information, the human counterparts of these genes may be more easily identified in an existing database of genetic information from people with a family history of MS, to determine if they contribute to MS susceptibility.

The mice generated in this study should provide new models with which to study the MS disease process and test potential treatments.
 

TARGETED RESEARCH

GENDER DIFFERENCES

Clues to the Cause of MS?

The influence of gender on MS may be a powerful one, and research indicates that gender strongly influences many autoimmune diseases. It is vital that we understand how the biology of gender exerts its influence, and for this reason, the Society has targeted this as an important area of exploration.

Researchers are investigating the intricate mechanisms that may be involved when sex hormones interact with the immune system. This frontier is one of the most exciting in MS research, given the implications for developing therapies involving these hormones, if indeed they can influence the course of MS.

Since targeting this area of research, the National MS Society has funded 11 large research grants on gender differences (including the following one new one), four smaller pilot projects, and 22 financial supplements to researchers adding explorations of gender differences to their existing MS research projects. The Society has also extended the reach of its gender initiative by collaborating with the National Institute of Allergy and Infectious Disease to fund research on sex-based differences in the immune response, and has committed up to $4 million to this effort.

Sex hormones may exert effects on the immune response in MS and may contribute to gender disparity.
 

Ioana R. Moldovan, MD, PhD
Cleveland Clinic Foundation
Cleveland, OH
Area: Northeast Ohio Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $147,555

Gender differences in immune responses in multiple sclerosis

Investigating differences in immune responses against nerve-insulating myelin between men and women with MS.

It has long been noted that women are two to three times more likely to develop MS than men. Growing evidence suggests that sex hormones exert effects on the immune response that influence MS and may be at least partially responsible for this gender disparity. Ioana Moldovan, MD, PhD, is exploring how sex hormones directly influence the immune system in MS.

Dr. Moldovan believes that the immune response in women with MS is skewed toward a destructive pattern, in which the immune cells called T cells release messenger chemicals (cytokines) that amplify the damaging effects on the nervous system. In men, the opposite occurs: T cells release protective cytokines that reduce immune damage. Dr. Moldovan is testing blood samples from men and women with MS for these different immune responses, and is also examining the effect of sex hormones on cytokine secretion from T cells grown in the laboratory.

Understanding gender differences in MS could lead to the design of specific treatment approaches that take advantage of hormonal influences on immune responses in MS.
 

NEUROPATHOLOGY

Nerve Tissue Destruction

Nerve signals are transmitted through the wire-like arm of nerve cells, called the nerve fiber or axon. Any disruption to the myelin that insulates the axon, or to the axon itself, can weaken or block these vital signals. Research from neuropathology studies indicate that the immune attack in MS not only damages myelin, but also axons. Investigators are working to determine how and when axons get damaged, and how to protect them.

Among the tools investigators are using to track nerve tissue damage in MS are new magnetic imaging technologies. These include MRS, which can detect levels of specific chemicals to monitor axonal damage, and diffusion tensor imaging (DTI), a sensitive monitor of changes in the brain.

The Society is currently funding 12 research neuropathology projects studying nerve tissue destruction in MS, including the following five new projects.

Investigators are working to determine how and when axons get damaged, and how to protect them.

Jayasri Das Sarma, PhD
University of Pennsylvania
Philadelphia, PA
Area: Greater Delaware Valley Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $147,555

The role of gap junctions in mouse hepatitis virus (MHV) induced demyelination

Exploring the idea that communication between cells in the brain can be disrupted by viral infection in MS-like disease.

The biological processes that lead to the loss of myelin, the insulation that coats nerve fibers, in an MS immune attack are not clear.

One factor may be the disruption of normal communication between cells. Jayasri Das Sarma, PhD, is exploring “connexin,” a key component in the “bridges” between cells called gap junctions. Gap junctions link brain cells called astrocytes to myelin-making cells known as oligodendrocytes.

Dr. Das Sarma is exploring the possibility that a viral infection may cause connexin to malfunction in MS, disrupting the gap junctions between brain cells and contributing to the destruction of myelin. She is exploring this possibility by taking oligodendrocytes and astrocytes from mice infected with the myelin-destroying mouse hepatitis virus (MHV) and using molecular techniques to define how this infection affects the structure and function of connexins and gap junctions.

These studies may determine a potential role for altered gap junction communication in the destruction of myelin that causes MS, and may identify new avenues for treatment.
 

James Y. Garbern, MD, PhD
Wayne State University
Detroit, MI
Area: Michigan Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $391,934

Models of axonal injury due to myelin disorders

Exploring the pathology that underlies the release of a brain chemical which is currently used to measure nerve cell damage in MS.

Growing evidence suggests that it is not only myelin – the material that insulates nerve fibers – that is injured in MS. Axons, or the nerve fibers themselves, are also damaged.

Axonal damage has been identified in both acute lesions (areas of active damage in the brain) and chronic ones (areas where damage took place in the past). Researchers have suggested that axons may be damaged due to direct inflammatory attack by the immune system, or secondarily, as a consequence of damage to myelin-forming cells called oligodendrocytes.

An advanced technology called magnetic resonance spectroscopy (MRS) identifies damage to axons in people with MS by detecting a drop in levels of N-acetyl aspartate (NAA), an axon-specific chemical whose full function is not yet clear. James Y. Garbern, MD, PhD, is utilizing MRS to study axonal damage in genetically altered mice born lacking a specific protein in myelin.

This model system has shown that communication between myelin and nerve fibers is important to the survival of both. Dr. Garbern is observing how well NAA levels correlate with axonal damage in these mice, and what role NAA levels play in the formation of myelin.

A better understanding of NAA and its impact on axonal and myelin integrity will shed new light on the damage caused by MS, and also help investigators interpret their MRS findings in people who have this disease.
 

Roland G. Henry, PhD
University of California at San Francisco
San Francisco, CA
Area: Northern California Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/06
Funding: $656,018

Diffusion tensor imaging in multiple sclerosis

Exploring the potential of a novel imaging technology in people in the earliest stages of MS.

A hallmark of MS is the damaged areas, called lesions, evident in the white matter of the brain and spinal cord. Lesions are the end result of the immune-system assault against the myelin sheath that covers nerve fibers (axons). Damage also occurs to the axons themselves, and recent evidence suggests that axonal damage can occur not only in lesions but also in normal-appearing brain tissue – areas where no lesions are apparent.

Although magnetic resonance imaging (MRI) has yielded important information regarding anatomical and pathological changes in MS, it is less sensitive to abnormalities in the non-lesion areas of the brain. Now a new technology, called diffusion tensor imaging (DTI), offers greater sensitivity to pathological changes in MS and some distinct advantages in studying the earliest phases of disease.

Roland G. Henry, PhD, is using DTI to visualize both the type and magnitude of structural changes taking place within the brains of a group of untreated people in the earliest stage of MS. These findings will provide a benchmark of early changes in both lesions and normal-appearing areas of the brain. Early and reliable identification of individuals at risk will allow a better under-standing of the evolution of disease and, perhaps, more timely intervention when little damage has occurred in people with MS.
 

Aaron J. Johnson, PhD
Mayo Clinic and Foundation
Rochester, MN
Area: Minnesota Chapter
Award: Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $110,120

Assessment of axonal injury induced by antiviral CD8+ T cells

Understanding the potential of immune cells that are activated by a virus to destroy nerve fibers in MS-like disease, and by implication, in MS.

The mechanisms leading up to the destruction of nerve fibers and subsequent physical impairment in people with MS are not yet understood. To acquire a better grasp of this process, Aaron J. Johnson, PhD, is studying an MS-like disease caused by infection of mice with Theiler’s virus. This virus produces chronic brain and spinal cord inflammation, motor deficits, and destruction of the myelin sheath (the protective coating that surrounds nerve fibers, or axons) and axons – all of which occur in MS.

Dr. Johnson’s team is investigating a set of immune T cells – CD8+ T cells – that have anti-virus activity and appear to be a critical link between inflammation and neurological impairment. The team is researching the underlying mechanisms by which CD8+ T cells destroy nerve fibers or impair their function.

This project offers great potential for better understanding the links between inflammatory immune events and the ultimate destruction of tissue in the central nervous system.
 

Jack H. Simon, MD, PhD
Univ. of Colorado Health Science Center
Denver, CO
Area: Colorado Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $319,972

Neuronal tract degeneration in the earliest stages of multiple sclerosis

Exploring damage to nerve fibers that may occur in people in the earliest stages of MS using advanced brain imaging techniques.

Until recently, MS was thought to be a disease characterized largely by the destruction of myelin, the insulating coating that protects nerve fibers. But the assault also is directed against the axon, the nerve fiber itself. This axonal injury can occur quite early in the disease process.

Looking closely at axonal damage may help clarify progressive and permanent disability in MS, since repair of axons is difficult to achieve. To that end, Jack H. Simon, MD, PhD, is examining degeneration of nerve “tracts” (long extensions of nerves – axons and myelin – in the nervous system.

Tract degeneration probably includes severe injury to the axon as well as myelin. Recent studies suggest that tract injury may occur in the earliest stages of disease, and may be initiated at the time when individual, small inflammatory MS lesions are seen.

Dr. Simon is using magnetic resonance imaging (MRI) to identify tract injuries in people at the earliest stages of MS and is observing their changes over time. Understanding these injuries, their progression, and their relationship to MS lesions may ultimately provide better understanding of the pathology of the disease and of the development of disability, and will also provide better methods to assess the efficacy of new MS therapies.
 

NERVOUS SYSTEM REPAIR

Restoring Brain Tissues

Now that therapeutic agents are available that can at least reduce the ongoing immune assault against nervous-system tissue in some forms of MS, the idea of trying to repair the damage is no longer a mere dream.

Decades of research into neurophysiology and the biology of glial cells have been laying the groundwork for finding ways to restore normal function in people with MS.

The Society is currently funding 10 investigations focusing on finding ways to stimulate replacement cells to repair myelin and nerve cells, or, as in the case of the following new project, identifying biological impediments that must be overcome if normal function is to be restored.
 

Wim J. Mandemakers, PhD
Stanford University Medical Center
Palo Alto, CA
Area: Silicon Valley Chapter
Award: Postdoctoral Fellowship
Term: 1/1/02 - 12/31/04
Funding: $119,725
Funded in full by a gift from the Alan Buegeleisen Research Fund

The identification of novel CNS myelin-associated proteins that inhibit axon out-growth

Looking for proteins in nerve fiber-insulating myelin that may inhibit the regeneration of nerve fibers in MS.

There is a growing awareness of the inter-dependent relationship between the elongated nerve fibers that transmit nerve signals and the myelin that coats them. When myelin in the brain and spinal cord is destroyed in MS, it can make the underlying nerve fiber vulnerable to damage. At the same time, however, recent research suggests that myelin in the brain and spinal cord can actually inhibit the regeneration of nerve fibers.

Myelin is made up of many different fats and proteins, and several myelin proteins have been identified that partially inhibit nerve fiber repair, but it is thought that more inhibitory factors remain to be identified in myelin. Dr. Mandemakers is applying state-of-the-art techniques to screen hundreds of myelin components for their potential role in inhibiting nerve fiber regeneration. This technique involves generating copies of antibodies that stick to specific myelin components and can thus prevent those myelin components from inhibiting the growth of nerve cells in tissue culture.

Relevant antibodies identified through this system can then be used to develop a potential therapy that will block nerve regeneration inhibitors so that nerve fibers damaged by MS can be repaired. This will hopefully lead to the recovery of function in people with MS.
 

IMMUNOLOGY

Why the Immune System Goes Awry

Better treatments and a cure are the ultimate goals of MS research, and perhaps no branch of investigation has born more fruit toward these goals than the study of the immune system. All four FDA-approved therapies for MS emerged from the growing understanding of how the immune system works and how it can be manipulated to suppress or regulate immune attacks.

Researchers funded by the Society are investigating many cells and proteins in the immune system whose complex interactions can spur on or suppress the immune attack.

By evaluating the importance of these components, we can find new and better ways to successfully treat MS.

The National MS Society is currently funding 126 research projects focusing on the immunological underpinnings of MS, including the following 24 new projects.
 

Christine Beeton, PhD
University of California, Irvine
Irvine, CA
Area: Orange County Chapter
Award: Postdoctoral Fellowship
Term: 8/1/01 - 7/31/04
Funding: $111,120

Therapy of autoimmune diseases by lymphocyte potassium channel blockers

Determining whether blocking ion channels in immune cells can improve MS-like disease in mice.

Immune cells called T lymphocytes, or T cells, play a pivotal role in initiating the immune attack against myelin, the tissue that surrounds and insulates nerve fibers, in MS.

Evidence suggests that tiny channels or pores in the T-cell membrane responsible for controlling the flow of potassium into and out of the cell are important in regulating the T-cell response in immune attacks. Christine Beeton, PhD, is investigating whether selectively blocking these channels can deactivate T cells and prevent them from reacting against myelin.

Dr. Beeton is isolating myelin-reactive T cells from rats and testing the ability of drugs used to block potassium channels in humans to inhibit T-cell activation. She is then determining whether these drugs can prevent or treat EAE, an MS-like disease, in laboratory rats.

Defining the role of T-cell potassium channels in EAE could lead to the use of potassium blockers as a novel treatment for MS.
 

Elizabeth P. Blankenhorn, PhD
MCP Hahnemann University
Philadelphia, PA
Area: Greater Delaware Valley Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $405,999

Correlation of immune response phenotypes with EAE genetic susceptibility

Linking genes that make mice susceptible to an MS-like disease to specific types of immune-system responses.

Genes are believed to play a significant role in susceptibility to MS, which is caused by an immune attack against the body’s own brain and spinal cord tissues. Researchers believe that many genes are involved and have clues to the location of some genes that might be involved. Efforts are under way to locate specific genes linked to immune characteristics that might explain the disease’s effect on the nervous system.

Elizabeth Blankenhorn, PhD, is exploring the genetic basis for immune mechanisms in three strains of rats that have different resistance and susceptibility to the MS-like disease EAE. She is searching for evidence to link specific immune traits – for instance, the ability of immune cells to recognize nervous tissue as “foreign” – with genes that influence susceptibility to disease. Ultimately, Dr. Blankenhorn hopes to piece together the individual immune effects of an array of genes that help determine susceptibility to disease.

Linking the function and location of EAE-related immune response genes may lead to clues to the human genes that confer susceptibility and resistance to MS.
 

Abigail C. Buenafe, PhD
Oregon Health Sciences University
Portland, OR
Area: Oregon Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $423,017

Molecular interactions of myelin basic protein-specific T cell receptor

Determining how immune cells recognize their myelin protein targets during the attack in MS-like disease.

T cells occupy a pivotal role in the body’s defense system. When they encounter an invading substance, they can launch an attack – setting up an inflammatory response.

Guiding these T cells are receptors (docking proteins on their surface), which help them distinguish between what is a foreign substance and what is “self,” or part of the body that should be protected from immune attack. But some T cells receptors mistake self proteins for foreign and provoke a destructive autoimmune process within the body. In MS, the self protein that is mistaken for foreign may be a protein in myelin, the substance that insulates nerve fibers.

Abigail C. Buenafe, PhD, is exploring how T cell receptors recognize their target at the molecular level. Using rat and mouse models, Dr. Buenafe is inducing a MS-like disease called EAE and then examining T cells that infiltrate the brain and spinal cord, looking specifically at their receptor proteins.

Understanding how T cells recognize and bind with targets may help design molecules that block this interaction, possibly preventing or stopping the immune attack in MS.
 

Guifang Cai, PhD
Brigham and Women's Hospital
Boston, MA
Area: Central New England Chapter
Award: Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $119,725

Immunoregulatory role of a suppressive costimulatory molecule, PD-1, in MS

Determining whether a molecule that can normally suppress certain immune attacks is abnormal in people with MS.

To trigger the immune response against nerve-insulating myelin in MS, immune cells known as T cells must first be activated by recognizing a piece of myelin. A second requirement for T cell activation is the binding of “costimulatory” molecules to special receptors, or docking proteins, on the T-cell surface. Once activated, T cells unleash chemicals that launch the destructive immune attack against myelin.

A recently discovered molecule called PD-1 has been shown to suppress activation of T cells when it binds to one of the costimulatory receptors. Through a series of experiments using immune cells from people who have MS, Guifang Cai, PhD, is examining whether PD-1 itself or the signal it generates is defective in people with MS, thus allowing T-cell activation and the attack against myelin to proceed.

Dr. Cai’s investigation may lead to a new target for stopping or even preventing the immune attack in MS.
 

John L. Croxford, PhD
Northwestern University
Chicago, IL
Area: Greater Illinois Chapter
Award: Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $119,725

Role of molecular mimicry in the initiation of central nervous system autoimmune disease

Investigating how viruses may activate immune cells in an MS-like disease in mice.

Most experts believe that MS results from a combination of factors in individuals who have a genetic susceptibility to the disease.

One factor may be an encounter with an infectious agent, such as a bacterium or virus, although no such agent has been proven to have a role in causing MS.

John L. Croxford, PhD, is focusing on the role of a virus in the induction of an MS-like disease in mice. In the normal immune system, specialized white blood cells called T cells recognize and mount an attack against invading viruses and bacteria. In people with MS, on the other hand, they can launch an assault against myelin, the protective sheathing around nerve fibers, and nerve fibers themselves.

These myelin-specific T cells may be activated by viral or bacterial proteins that have structures similar to myelin. This concept is called “molecular mimicry,” and it may explain how viral infections could prompt the immune system to recognize and attack its own (or self) tissue.

To test this idea, Dr. Croxford is infecting mice with variants of a virus that has components that are similar to a myelin protein. He is then examining the extent of MS-like disease generated by immune cells that recognize the myelin mimics in the virus and that subsequently target myelin itself. This study can provide important insights into how MS is triggered, and help pave the way for developing new ways to combat it.
 

Suhayl Dhib-Jalbut, MD
University of Maryland
Baltimore, MD
Area: Maryland Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $461,624

Interferon-beta gene therapy in an animal model of MS

Testing a novel method of delivering interferon-beta into the brain in a mouse model of MS.

Interferon beta is a natural messenger chemical of the immune system that has formed the basis of several immuneregulating drugs approved to treat MS. The drugs are administered by injection under the skin or into the muscle, both of which may reduce the dose of the drug that reaches the brain or spinal cord, where the MS-associated immune attack occurs. Suhayl Dhib-Jalbut, MD, is testing the effectiveness of a new approach that may deliver interferon beta directly into the brain.

Preliminary evidence confirms that bone marrow cells removed from mice and then re-injected into the bloodstream travel to the brain. Dr. Dhib-Jalbut is inserting into bone marrow cells a gene that stimulates the cells to produce interferon beta, and injecting these into mice with an MS-like disease called EAE. Once these cells reach the brain, they should produce greater amounts of the drug than is possible with current therapies. He is then testing immune characteristics and symptoms of the treated mice to determine whether this novel strategy succeeds.

This preliminary study, if successful, may pave the way toward similar strategies to deliver important immune-regulating drugs directly to the area of immune activity in people with MS.

This study may pave the way toward strategies to deliver immune-regulating drugs directly to the area of immune activity in MS.
 

Asim Diab, MD, PhD
Univ. of Texas Southwestern Medical Center
Dallas, TX
Area: Lone Star Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $135,469

Role of peroxisome proliferator-activated receptors in CNS autoimmune demyelination

Evaluating the immune effects of a novel compound and whether it can inhibit MS-like disease in mice.

The immune attack in MS sets off a cascade of events that lead to inflammation and destruction of tissue in the brain and spinal cord. Although several therapies are somewhat effective against MS, there is still no therapy that can stop the disease. Most agents regulate the immune response in a global, rather than specific, manner.

An attractive alternative would be to devise a therapeutic approach that specifically activates pathways that regulate the immune response. Naturally occurring molecules called “peroxisome proliferator-activated re-ceptors” (PPARs) appear to be important in modulating inflammation and the growth and proliferation of immune cells.

Studies have demonstrated that PPARs can improve animal model diseases that involve an immune attack similar to MS. By manipulating conditions in mice with the MS-like disease called EAE, Asim Diab, MD, PhD, is studying the mechanisms by which these receptors can modulate the immune response.

Understanding how PPARs influence central nervous system inflammation may offer a new therapeutic approach for MS.
 

Bonnie N. Dittel, PhD
The Blood Center of Southeastern Wisconsin
Milwaukee, WI
Area: Wisconsin Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $483,533

Immune regulation by B cells in the recovery from EAE

Determining how immune B cells may participate in recovery from MS-like disease.

In a special strain of mice used in MS research, the experimental MS-like disease called EAE results in paralysis and other neurological symptoms. Within a few weeks, the mice spontaneously recover. However, Bonnie Dittel, PhD, has observed that mice deficient in the immune cells called B cells do not recover from EAE in this animal model, suggesting that B cells regulate the recovery process.

B cells have two roles in the immune system. First, they make antibodies, proteins that mark substances for destruction by the immune system. Second, they engulf small pieces of disease-causing material and then “present” them to other immune cells called T cells, triggering an immune response. Dr. Dittel is unraveling which B cell functions are required for EAE recovery in these mice.

The logical next step would be to study similar B cell functions in people with MS to determine whether defects in B cell functioning are responsible for the inability to recover from MS attacks.
 

Martin E. Dorf, PhD
Harvard Medical School
Boston, MA
Area: Central New England Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $390,691

Mechanisms of chemokine-mediated astrocyte activation

Investigating how immune messenger chemicals interact with specific brain cells during the immune attack in MS.

The immune attack in MS involves special messenger molecules that recruit immune cells from the blood into the brain. These molecules – called “chemokines” – interact in a complex manner with the other cells in the central nervous system, such as astrocytes, cells that perform several support and “housekeeping” functions in the brain and spinal cord.

Astrocytes may also play an active role in the destructive immune attack. Far from being “innocent bystanders,” astrocytes may amplify chemokine responses and prolong the attack. Martin E. Dorf, PhD, is analyzing the biological effects that occur after chemokines stimulate astrocytes. He is examining the interaction between chemokines and astrocytes in human cells in the laboratory, and is also searching for a way to inhibit the stimulation of chemokines by astrocytes.

These studies should provide valuable insights into the nature of chemokine production, paving the way for new therapies that may alleviate MS attacks.
 

Andrea E. Edling, PhD
Cleveland Clinic Foundation
Cleveland, OH
Area: Northeast Ohio Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $129,565

Bone marrow regeneration of auto-reactivity in experimental allergic encephalo-myelitis

Testing whether persistence of the immune attack in chronic MS-like disease is affected by factors in bone marrow cells.

Studies indicate that the immune attack in MS involves immune cells, known as T cells, attacking proteins in myelin, the protective material that coats nerve fibers. Andrea E. Edling, PhD, believes that in MS and EAE (an MS-like disease in mice), T cells respond to continually attack new myelin proteins, perpetuating inflammation and leading to chronic disease. She is seeking evidence that chronic disease is due to a process that takes place within bone marrow, where a “memory” ensures a continual production of T cells that target myelin.

Dr. Edling is transplanting bone marrow cells into mice with EAE. She is treating these cells with a green fluorescent protein, and then observing their response to myelin proteins, and how this response helps per-petuate the MS-like disease over time.

Confirming the sequence of events that perpetuate the disease state might lead to the development of specific therapies that could be delivered after the onset of clinical disease, preventing further production of T cells and thereby interrupting progression of MS.
 

Adam Elhofy, PhD
Northwestern University Medical School
Chicago, IL
Area: Greater Illinois Chapter
Award: Postdoctoral Fellowship
Term: 9/1/01 - 8/31/04
Funding: $119,725

Role of monocyte chemotactic protein-1, MCP-1, in autoimmune encephalomyelitis

Investigating the role of certain immune molecules in decreasing the severity of MS-like disease.

In the initial stages of MS, immune cells called T cells breech the brain’s protective wall of cells and blood vessels and initiate an immune attack that destroys nervous tissue.

Attractant molecules called chemokines are believed to play a role in this process and may either enhance or suppress immune responses.

Adam Elhofy, PhD, has noted that in a particular mouse strain genetically engineered to overproduce a chemokine called MCP-1, the severity of an MS-like disease called EAE is markedly reduced. Dr. Elhofy is testing whether MCP-1 skews the immune reaction that takes place in the brain toward a protective, rather than destructive, response. His idea is that MCP-1 may reduce the sensitivity f destructive T cells to an immune chemical called interleukin-4, allowing protective T cells to proliferate.

Clarifying the function of important chemokines such as MCP-1 in EAE will contribute to the development of therapies that can protect against multiple sclerosis.
 

Claude P. Genain, MD
University of California at San Francisco
San Francisco, CA
Area: Northern California Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $505,178

Molecular analysis of demyelinating antibody responses in EAE

Characterizing immune antibodies that play a role in the destruction of nerve-insulating myelin in MS-like disease.

Claude Genain, MD, is studying the role of immune proteins called antibodies in the immune-mediated attack on myelin, the nerve tissue destroyed in MS. Antibodies mark harmful invaders, such as viruses or bacteria, for destruction. In MS, however, antibodies, as well as the more often studied immune T cells, may turn against myelin. Working with animals with an MS-like disease called EAE, Dr. Genain is focusing on a group of anti-bodies directed against a myelin protein called myelin oligodendrocyte glycoprotein (MOG). His experiments are designed to determine the quantity of anti-MOG antibodies made, to pinpoint the genes that produce them, and identify the antibodies that may actually damage myelin.

Dr. Genain’s continuing research in this area may suggest ways to modify anti-MOG antibodies so that they bind to myelin without damaging it, thereby blocking the myelin destruction that causes MS.
 

Susanna F. Greer, PhD
University of North Carolina at Chapel Hill
Chapel Hill, NC
Area: Eastern No. Carolina Chapter
Award: Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $119,725

Promoter specific control of CIITA regulates MHC class II in demyelination

Understanding the mechanisms by which certain cell-surface molecules help activate the immune response in MS-like disease.

To launch their attack on myelin, the membrane of fats and proteins that insulates nerve fibers, immune cells called T cells recognize tiny pieces of myelin proteins that have been engulfed by other immune cells called “antigen-presenting cells.” T cells can only recognize and attach to myelin fragments on antigen-presenting cells that carry a molecular “tag” called class II major histocompatibility complex (MHC). MHC is controlled by yet another protein called CIITA.

Susanna Greer, PhD, is investigating how CIITA regulates the presence of MHC in different types of immune cells, including antigen-presenting cells. Her goal is to deter-mine whether suppressing CIITA, and therefore MHC, can control the onset or progression of an MS-like disease of mice called
EAE.

Understanding the mechanisms by which CITTA controls MHC, and thus antigen presentation and immune destruction of myelin, may suggest therapeutic strategies to treat MS that specifically block immune activation by myelin.
 

Guy Hermans, PhD
Stanford Medical Center
Palo Alto, CA
Area: Silicon Valley Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/02
Funding: $41,211

Use of co-stimulatory molecules as DNA co-vaccines as a therapy for EAE

Investigating the possibility of using gene vaccines to regulate the immune response in MS-like disease.

Although several drugs to treat MS have been approved, none halts the disease or reverses its damage. The search for improved therapies continues, and one that is under investigation is a DNA vaccine, which is being developed for MS based on the proteins under attack in the brains of people with MS.

Included in the vaccine is a specific immune protein component called interleukin 4, which prevents the immune system from mounting an inflammatory response characteristic of MS. This vaccine has prevented disease in a mouse model of MS called EAE.

Guy Hermans, PhD, is creating new potential DNA vaccines incorporating additional molecules that may further help regulate the immune response, with the goal of finding a mix that produces maximal effectiveness against EAE, as a model for similar results in MS. He is investigating the potential of these mixes using DNA chips, a technology that enables scientists to look at the effect of DNA vaccination on thousands of immune system components simultaneously. If successful, this type of DNA vaccination may be a novel therapeutic approach in MS.
 

Thomas E. Lane, PhD
University of California, Irvine
Irvine, CA
Area: Orange County Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $337,641

Chemokines & chemokine receptors and their roles in viral-induced demyelination

Investigating factors that regulate how immune cells invade the central nervous system in MS-like disease.

MS is marked by the gradual destruction of the myelin sheath that surrounds nerve fibers and nerve fibers themselves. Considerable research has been directed at discovering how immune cells invade the central nervous system (CNS) and attack myelin. Thomas E. Lane, PhD, is working to identify factors that regulate immune cell invasion of the CNS.

Both genetic and environmental influences – such as viruses – may contribute to the development of MS. Dr. Lane and his colleagues are studying the mouse hepatitis virus (MHV), which causes MS-like symptoms caused by an immune attack against brain tissues. They have established that MHV infection of the CNS produces messenger chemicals, called chemokines, that rev up the immune attack. Now they are investigating specific chemokines and their receptors (docking proteins on the surface of cells) to determine their roles in CNS inflammation, and exploring how molecules that block their activity may enhance myelin repair.

This approach may lead to the development of treatments that block the immune attack and prevent myelin loss in MS.
 

Roy A. Mariuzza, PhD
University of Maryland Biotech Institute
Rockville, MD
Area: National Capital Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/06
Funding: $707,740

Structural basis of molecular mimicry in multiple sclerosis

Determining the structure of molecules involved in the immune attack against the nervous system in MS.

One way to thwart MS is to design a drug that stops immune cells called T cells from attacking nerve-insulating myelin. Knowing the precise shapes of molecules involved in the immune attack is crucial to this aim.

To this end, Roy Mariuzza, PhD, is using a technique called X-ray crystallography to define the three-dimensional structures of two receptors, or docking proteins, believed to be involved in MS immune attacks: the T-cell receptor (TCR) that binds to a component of myelin called myelin basic protein (MBP) to initiate an immune response, and the “MHC complex” involved in how MBP is presented to T cells. Dr. Mariuzza is also studying the structures of selected viral and bacterial proteins, which research suggests may be responsible for triggering the attack against myelin.

So far, he has elucidated the structures of several viral toxins called “superantigens” that activate large numbers of T cells, including those that react against myelin.

Characterizing the 3-D structure of these key players in the immune attack will allow the design of drugs that will precisely block the binding of MBP to T cells and prevent a primary step in the immune response in MS.

Til R. Menge, MD
University of California at San Francisco
San Francisco, CA
Area: Northern California Chapter
Award: Postdoctoral Fellowship
Term: 10/01/01 - 9/30/04
Funding: $143,860

Structural basis for antibody responses to myelin/oligodendrocyte glycoprotein

Characterizing the structure and immune response to a myelin protein that may be a target for the immune attack in MS.

Some research suggests that immune proteins called antibodies may contribute to the destruction of myelin, the insulating covering of nerve fibers, in MS. Antibodies bind to disease-causing invaders, such bacteria, marking them as targets for immune cells. In MS, however, antibodies may turn against myelin.

One of their targets may be a myelin protein called myelin oligodendrocyte glycoprotein (MOG). Til R. Menge, MD, is examining these anti-MOG antibodies in detail to learn more about their possible role in MS.

Dr. Menge is generating anti-MOG antibodies made in an animal model of MS and then studying the diversity in molecular structure among these antibodies using a technique called X-ray crystallography. Dr. Menge’s ultimate goal is to characterize the interaction between anti-MOG antibodies and MOG that may lead to demyelination.

If anti-MOG antibodies turn out to play a significant role in the myelin destruction that occurs in MS, having a blueprint of their molecular structure will help in the design of drugs that can block their activity to help prevent or control neurological damage.
 

Stephen D. Miller, PhD
Northwestern University
Chicago, IL
Area: Greater Illinois Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $327,433

Mechanisms of therapeutic blockade of CD154 in prevention of relapsing EAE

Exploring ways to block the interaction of immune cells to stop ongoing immune attacks in MS-like disease, and ultimately in MS.

Scientists believe that as the MS immune attack in the brain and spinal cord destroys the myelin coating around nerve fibers, new immune targets, called antigens – possibly released from the injured myelin itself – provoke the immune system to continue its attack, thereby perpetuating the disease.

One strategy for the treatment of MS is to intervene at the molecular level and prevent crucial interactions of specific immune cells that are involved in this process. One immune-cell interaction that holds significant potential to serve as a therapeutic target is that which occurs between the immune cell surface molecules CD154 and CD40. The interaction of these two “costimulatory” molecules can be inhibited by administering antibodies.

The advantage of this approach is that it affects those activated immune cells that are involved in the ongoing disease process, even the recruitment of additional immune cells targeted to new antigens.

Stephen D. Miller, PhD, has shown that using antibodies to block the interaction of CD154 and CD40 can prevent relapses and progression of EAE, an MS-like disease in mice. He is now investigating how this antibody changes different phases of the immune attack as a first step toward weighing its potential relevance to treating the human forms of multiple sclerosis.
 

Kakuri Omari, PhD
Albert Einstein College of Medicine
Bronx, NY
Area: New York City Chapter
Award: Postdoctoral Fellowship
Term: 9/1/01 - 8/31/04
Funding: $111,120

Chemokine receptor expression in the central nervous system

Exploring the presence and function of immune-system molecules and their docking proteins in MS brain lesions.

During the early stages of MS, immune cells known as T cells migrate from the bloodstream into the brain and initiate an immune response against nervous-system tissues.

Messenger chemicals called cytokines rev up this immune response, and research suggests that other immune chemicals called chemokines attract the T cells into the brain.

Kakuri Omari, PhD, is looking closely at the receptors, or docking proteins, for two chemokines (CCR2 and CCR5) recently implicated in the MS disease process.

Using brain tissue collected from people with MS, Dr. Omari is isolating brain cells, especially those near MS lesions (damaged areas), to see how many carry CCR2 and CCR5 receptors. He is also treating brain cells with various cytokines known to be associated with the MS immune attack, to see which may cause the receptors to appear and begin their activity of attracting immune cells into the brain. Dr. Omari is also analyzing the cells to see if there is a genetic predisposition for the two receptors to appear on the cells.

The information gained in these experiments may clarify the complex role of chemokines in the process of tissue damage in MS.
 

Murali Ramanathan, PhD
State University of New York at Buffalo
Buffalo, NY
Area: W. New York/N.W. Penn. Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/03
Funding: $534,823

The study of mRNA expression profiles in multiple sclerosis

Identifying changes in the immune systems of people with MS that may help to predict neurologic damage, disability and response to therapy.

Each protein that is involved in the immune attack in MS has a gene that carries instructions for its activity; these genes might be particularly useful as markers of disease activity in MS.

Utilizing DNA arrays – a powerful tool that allows simultaneous measurement of a large amount of genetic material – Murali Ramanathan, PhD, is tracking the immune changes in the blood of people with MS. He is also using magnetic resonance imaging (MRI) and neurological tests to monitor the disease state clinically. One of Dr. Ramanathan’s primary goals is to identify molecular changes in immune activity that can predict changes in brain tissue and neurological disability.

Other aspects of the study include comparing gene patterns in people with relapsing-remitting MS before and after treatment with interferon beta, and analyzing genetic patterns during and after a relapse.

The findings from this study should provide valuable insights into the immune changes that occur during the clinical course of MS. Another potential outcome is the development of a method that assesses individual responses to drug therapies, such as interferon beta.

Jayagopala Reddy, PhD
Brigham and Women's Hospital
Boston, MA
Area: Central New England Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $129,566

Analysis of endogenous myelin proteolipid protein-reactive T cell repertoire

Exploring aspects of immune responses that might account for why the immune system attacks the body’s own tissues in people with MS.

In MS, T cells that are programmed to react against nerve-insulating myelin initiate an immune response against this tissue. However, many people who do not develop MS also possess these myelin-reactive T cells. Jayagopala Reddy, PhD, is exploring why these T cells go on attack in some individuals but not in others by focusing on two strains of mice that are susceptible to developing an MS-like disease called EAE.

Dr. Reddy is focusing on T cells that react against a myelin component called proteolipid protein (PLP) in the mice. Like humans, these mice have normal circulating T cells that react to PLP, but they do not develop the disease unless it is induced experimentally.

His experiments are designed to decipher whether normal circulating PLP-reactive T cells help induce EAE or provide resistance to it, and to explore the immune processes that are involved. Dr. Reddy is also investigating the trigger that causes this population of cells to proliferate in EAE, which could be a viral or bacterial protein or even a protein normally present in the body.

This study could answer fundamental questions about how MS is initiated as well as shed light on MS susceptibility.
 

John R. Richert, MD
Georgetown University Medical Center
Washington, DC
Area: National Capital Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $438,976

Development of small organic molecules that bind to HLA

Designing small molecules that may be able to block the immune attack against myelin in MS.

John R. Richert, MD, is continuing his innovative efforts to design small molecules that can stop immune cells called T cells from reacting against nerve-insulating myelin, the catalyst for MS. This reaction is triggered when immune cells called antigen-presenting cells (APCs) engulf myelin fragment that bear an identification molecule called HLA on their surface. When T cells “recognize” myelin fragments presented by the APC and bind to HLA, they unleash an attack against myelin.

Dr. Richert has generated molecular models of two HLA types commonly found in people with MS as well as models of myelin basic protein (MBP) and the T-cell docking protein with which HLA and MBP interact.

He is now searching several laboratories’ databases for molecules that match these configurations and have the potential to block the T cell’s reaction against MBP.

Once identified, promising molecules can be tested in mice and eventually in humans for their ability to prevent myelin-directed immune responses.
 

John H. Russell, PhD
Washington University
Saint Louis, MO
Area: Gateway Area Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/03
Funding: $248,076

Tumor necrosis factor receptor family molecules and EAE pathogenesis

Examining immune molecules in MS-like disease that may be involved in the death of myelin-making cells in MS.

MS involves an immune-system attack on brain and spinal cord tissue. John H. Russell, PhD, is focusing on two immune molecules involved in this attack, FasL and tumor necrosis factor (TNF). These molecules appear to play an important role in EAE, an MS-like disease in mice. Dr. Russell is examining their interaction with the receptors, or docking proteins, on the surface of brain cells through which they cause damage.

An important question is whether TNF and FasL are the major stimulators of disease in the central nervous system, or whether other molecules contribute. Dr. Russell is taking an innovative approach to tease out the answer, using mice genetically engineered to lack receptors for TNF and FasL in their brain cells.

Dr. Russell is examining these mice to determine the effect of deleting these molecules on different cell types, and to see which brain cells are most vulnerable to attack.

If FasL and TNF turn out to be dominant molecules in the mouse model of MS-like disease, this may provide the framework for future strategies to treat MS.
 

Roel C. van der Veen, PhD
University of Southern California
Los Angeles, CA
Area: Southern California Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $479,780

Regulation of immune responses by nitric oxide

Examining the role of a molecule that may prove to be an important regulator of the immune attack in MS.

Nitric oxide (NO) is an important molecule that acts throughout the body to regulate a broad scope of physiological processes.

Among its other actions, NO appears to play a significant role in determining the intensity of immune responses and may play a role in the destructive immune attack in MS.

To further assess this role, Roel C. van der Veen, PhD, and his team are studying an MS-like disease in mice, called EAE. Mice deficient in a molecule called “superoxide-producing enzyme” (which normally reduces NO levels) have higher than normal amounts of NO and are resistant to EAE. Those with normal amounts of the enzyme have normal NO levels and are susceptible to EAE. Because of this key difference, these animals serve as an important resource to study the impact of NO on disease. Dr. van der Veen is also tracing what happens to superoxide-producing enzyme during the immune attack on brain tissue.

Teasing out the specific role of nitric oxide in the immune responses that lead either to EAE or to its resistance will add substantially to our understanding of this molecule, and its potential role in people with MS.
 

GLIAL CELL/MYELIN BIOLOGY

Can Myelin Be Repaired?

Recent discoveries are making the biology of glial cells an increasingly exciting area. Exploring glia, which include cells in the nervous system that make myelin, the coating that insulates and protects nerve fibers, has always been a cornerstone of MS research. Myelin, and cells that make it, appear to be the main target of the immune attack in MS.

Researchers are finding, however, that certain cells resident in our bodies may have potential to play a role in myelin repair. Many investigators are looking at immature myelin-making cells, known as “progenitors” or “precursors,” to determine if they can be stimulated to repair myelin. Investigators working in this field are also working to identify how glial cells become targets in MS, and how they might be protected.

The Society is currently funding 61 research projects in glial cell/myelin biology, including the following 12 new projects.
 

Glyn Dawson, PhD
University of Chicago
Chicago, IL
Area: Greater Illinois Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $387,713

Role of ceramide in oligodendrocyte cell death

Investigating a molecule that may contribute to the death of myelin-making cells in MS and testing compounds that may inhibit it.

In MS, the immune system mistakenly attacks myelin, the insulating sheath on nerve fibers, as well as the myelin-making cells called oligodendrocytes. Instrumental in this immune attack is tumor necrosis factor-alpha (TNF-alpha), a messenger chemical released by immune cells that amplifies the immune response. Glyn Dawson, PhD, is investigating how TNF-alpha stimulates a complex cascade of events inside oligodendrocytes that leads to their self-destruction. This may be one mechanism that accounts for the lack of myelin repair in MS.

When TNF-alpha binds to an oligodendrocyte’s outer surface, or membrane, this in-creases the level of a fat-like lipid called ceramide inside the cell and activates oligodendrocyte proteins. Increased ceramide and proteins disrupts manufacture of myelin. Dr. Dawson is testing whether various com-pounds can inhibit ceramide, allowing oli-godendrocytes to resume myelin production.

This research should help scientists identify steps involved in myelin destruction and find ways to protect oligodendrocytes from the immune attack.
 

Yue Feng, MD, PhD
Emory University
Atlanta, GA
Area: Georgia Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $400,016

Controlling myelin basic protein expression and CNS myelination by the QKI protein

Investigating a protein to understand its function in myelin formation and its potential role in myelin repair.

Myelin basic protein (MBP) is a pivotal molecule in MS. It is essential to the formation of myelin – the material that surrounds and protects nerve fibers – and is also believed to be a prime target for the immune-system attack that underlies the disease.

An intricate molecular interaction controls the production of MBP. One of the key players is believed to be the QKI protein, which is essential to the growth of myelin-producing cells called oligodendrocytes. As Yue Feng, MD, PhD, has observed in previous studies, QKI works together with various signaling molecules and cellular messengers to form myelin.

She is now focusing on identifying the specific mechanisms involved in the regulation of the QKI protein and its interaction with MBP. In so doing, she will also test the idea that elevating QKI activity can increase oligodendrocyte development and myelin for-mation.

If this proves to be the case, it may pave the way for devising new therapeutic strategies to enhance remyelination – or myelin repair – in people with MS.
 

Donna E. Hansel, MD, PhD
Erasmus University Rotterdam
Rotterdam, Netherlands
Award: Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $107,620

Identification of neuronally-derived molecules that induce gene expression in Schwann cells

Identifying molecules in nerve fibers that may be able to activate the repair of myelin, the nerve-fiber insulation destroyed by MS.

Many researchers are searching for ways to stimulate oligodendrocytes – the cells that make nerve-insulating myelin in the brain and spinal cord – to replace the myelin destroyed in MS. Understanding the signals that control myelin production in these cells is vital to this effort. Donna Hansel, MD, PhD, is searching for clues to these signals in oligodendrocytes by investigating those that turn on myelin production in Schwann cells, the myelin-making cells located outside the brain and spinal cord, because Schwann cells are easier to study and manipulate.

Previous research has identified a Schwann cell protein called Oct-6 that appears to regulate myelin growth. Dr. Hansel has identified an “enhancer” protein that helps activate the genes that control Oct-6. In this study, she is investigating the signaling molecules released by nerve fibers that activate the Oct-6 gene in conjunction with the Oct-6 enhancer.

Defining the complex interactions of these proteins in Schwann cells may lead to insights into the process of myelin production in oligodendrocytes, which is crucial to finding ways to enhance myelin repair in MS.
 

John Kamholz, MD, PhD
Wayne State University
Detroit, MI
Area: Michigan Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $413,477

The role of homeodomain protein, Gtx, in oligodendrocyte differentiation

Investigating the role of a newly identified protein in the formation of myelin, the nerve-fiber coating destroyed by MS.

A recently discovered protein called GTX may hold clues to how myelin, the sheath of fats and proteins that insulates nerve fibers, is formed. John Kamholz, MD, PhD, is investigating a possible structural role for GTX in myelin formation and maintenance by oligodendrocytes, the cells that produce myelin in the brain and spinal cord.

Dr. Kamholz is using mice in which the genes for GTX have been “knocked out,” or inactivated. The oligodendrocytes of these mice do not produce GTX, and they develop a progressive neurological disorder that affects their coordination. Dr. Kamholz’s experiments are aimed at determining how the absence of GTX affects myelin form and function and how it may cause clinical symptoms similar to those in MS.

Understanding the role of GTX in myelin formation could suggest ways in which this protein could be manipulated to restore the myelin that is destroyed in MS.
 

Robert W. Ledeen, PhD
University of Medicine and Dentistry of New Jersey
Newark, NJ
Area: Greater North Jersey Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/03
Funding: $297,902

N-acetylaspartate in myelin formation and demyelination

Determining the role of a brain chemical used by researchers to measure damage to nerve cells in MS. MS destroys myelin, the compact membrane that insulates neurons, or nerve cells.

Although myelin is repaired to a certain extent in the brain, it cannot keep up with on-going damage caused by MS. An amino acid in neurons called NAA (n-acetyl aspartate), which is often used to track nerve fiber damage, may contribute to myelin damage and lack of myelin recovery in MS, but its exact role is not known.

In this project, Robert W. Ledeen, PhD, is determining the exact role of NAA in both myelin formation and maintenance. Among the methods he is using, Dr. Ledeen is generating mice that lack the genes to produce NAA and searching for signs of abnormal myelin function. He is also tracing the path of NAA from neurons as it is taken up and incorporated into their myelin coating.

Identifying factors that contribute to myelin damage and the inability to repair it in MS may lead to strategies to neutralize these factors and reduce the neurological consequences of MS.
 

Sung Joong Lee, PhD
University of California at San Diego
La Jolla, CA
Area: San Diego Area Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $119,725

The role of glial cell-specific NF-kappa B activation in EAE

Investigating the role of an immune molecule that may play a role in the death of myelin-making cells in MS.

Recent studies have shown that levels of a molecule called nuclear factor-kappa B (NF), which is required to induce immune re-ponses, is increased in oligodendrocytes – cells that produce the myelin sheath that insulates nerve fibers – at the edges of MS lesions.

NF is also required for the production of inflammatory immune chemicals by brain cells called astrocytes. Using the MS-like disease EAE in mice, Sung Joong Lee, PhD, is defining the role of this molecule – and the molecules that stimulate NF production during inflammation – in the destructive immune response against myelin that is the hallmark of MS.

Pinpointing the molecular signals within brain cells that contribute to inflammation may lead to unique therapies to disarm these signals and prevent the immune response that leads to MS.
 

Robin Miskimins, PhD
University of South Dakota
Vermillion, SD
Area: Dakota Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $327,403

Cell cycle control in oligodendrocyte development

Examining the role of a protein in the development of myelin-making cells and the formation of myelin.

Oligodendrocytes are cells in the brain and spinal cord that manufacture myelin, the coating of proteins and fats that insulates nerve fibers and is destroyed in MS. Oligodendrocytes develop from immature cells called precursors. After dividing several times, the precursors suddenly stop growing and begin producing myelin.

In previous research, Robin Miskimins, PhD, found that a protein called p27 may signal the precursors to start myelin production, because levels of this protein increase inside the precursors as their growth ceases.

In this study, she is now defining the exact role of p27 in oligodendrocyte maturation.

Dr. Miskimins suspects that p27 turns on the genes, or molecular blueprints, that control the manufacture of myelin basic protein, a key component of the myelin sheath.

Understanding the signals and processes that trigger myelin production in oligodendrocytes may lead to strategies to initiate myelin repair in people with MS.
 

Jacqueline K. Morris, PhD
Cleveland Clinic Foundation
Cleveland, OH
Area: Northeast Ohio Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $147,556

The molecular mechanisms that control myelination

Determining the biological machinery behind the formation of myelin in the central nervous system.

In MS, the myelin insulation that surrounds axons, or nerve fibers, is destroyed by an attack by the body’s own immune system, and nerve fibers themselves can also be destroyed. Myelin is formed by cells in the brain and spinal cord known as oligodendrocytes. Because new myelin can be formed in some MS lesions, loss of myelin is not inevitably permanent. In fact, failure of myelin to regrow may be due to a miscommunication between oligodendrocytes and nerve fibers.

Looking at animals or organisms more primitive than mammals can help answer questions regarding the fundamental steps involved in myelin formation. Their nervous systems are relatively simple and easier to understand and manipulate. Zebrafish – a common aquarium species – has played a key role in studies of myelin development.

Working in a laboratory at the Cleveland Clinic – an institution whose investigators explore the most fundamental aspects of myelination to the most clinically relevant issues of tissue damage in MS – Jacqueline K. Morris, PhD, is exploring how myelin forms in the zebrafish brain, and how oligodendrocytes repair myelin following damage. She is making specific genetic mutations to identify possible defects in myelin formation or oligodendrocyte development that result from such mutations, with hopes of finding genes involved in myelin formation.

These studies will add to our understanding of how myelin normally forms and how it can be repaired in people with MS.
 

Brian Popko, PhD
University of North Carolina at Chapel Hill
Chapel Hill, NC
Area: Eastern No. Carolina Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $512,087

Global gene expression analysis of developing & perturbed oligodendrocytes

Identifying genes that may be important to the growth and development of myelin-making cells.

Oligodendrocytes are cells in the brain and spinal cord responsible for the manufacture and maintenance of myelin, which protects nerve fibers. Ample evidence suggests that these cells are a primary target of the immune attack in MS. Therefore, a comprehensive understanding of oligodendrocytes is critical to finding ways to stimulate myelin repair following injury.

It is now possible to characterize the genes that regulate oligodendrocyte activities using new “gene-chip” technology, in which researchers can obtain information about tens of thousands of genes at once. Capitalizing on this ability, Brian Popko, PhD, is defining those genes that are relevant to oligodendrocytes – looking at patterns of genetic material associated with normal oligodendrocyte development (leading to the formation of myelin) and comparing those with gene patterns that reflect the effects of myelin damage and repair.

Data from this innovative study may be used to design therapeutic approaches to promote myelin repair in people with MS.
 

Mengsheng Qiu, PhD
University of Louisville
Louisville, KY
Area: Kentucky Southeastern Indiana
Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $341,043

Lineage analyses and transcription control of oligodendrocyte genesis

Understanding the origins of myelin-making cells, and what factors are involved in their growth and development.

Oligodendrocytes, which are found in all parts of the brain and spinal cord, are the cells that manufacture myelin, which is the insulating covering of nerve fibers, or axons.

When oligodendrocytes and myelin are progressively destroyed by the immune attack in MS, the function of nerve fibers becomes significantly impaired.

Many therapeutic approaches in MS are directed at halting the immune attack that leads to myelin loss. But another strategy is to stimulate the regeneration of oligodendrocytes to repair myelin. That is the direction that Mengsheng Qiu, PhD, is pursuing. But this requires a more complete understanding of the origins of oligodendrocytes. Dr. Qiu and his team have found that two genes may be responsible for the development of oligodendrocytes, and are now testing this idea in mice engineered to lack these genes. They are also investigating factors that control when these genes turn on, and are seeking ways to manipulate the genes so that they regenerate oligodendrocytes.

These investigations will enhance the understanding of the early origins of oligodendrocytes, opening up the possibility for novel therapeutic methods to enhance myelin repair in MS.
 

Bridget Shafit-Zagardo, PhD
Albert Einstein College of Medicine
Bronx, NY
Area: New York City Chapter
Award: Research Grant
Term: 9/30/01 - 9/30/04
Funding: $402,636

Survival factors for human oligodendrocytes: implications for MS

Studying molecules that may have the power to protect myelin-making cells from dysfunction and death in MS.

Oligodendrocytes are cells that form myelin, the substance that insulates and protects nerve fibers. The survival of these cells is essential for normal neurologic function, which is why it is so important to understand what happens to immature and mature oligodendrocytes during and after the immune-system attack on brain and spinal cord tissue in MS.

Toward that aim, Bridget Shafit-Zagardo, PhD, and her team are working to identify genes that activate and maintain oligodendrocytes during the formation of myelin. The gene for one protein in particular, growth arrest-specific protein 6 (gas6), appears to play a pivotal role in protecting oligodendrocytes from cell dysfunction or death during development.

Dr. Shafit-Zagardo is examining the effect of this protein on the growth of oligodendrocytes from humans with MS and from mice with the MS-like disease EAE.

The information gained from these experiments should provide valuable insight regarding the developmental genes that regulate oligodendrocytes. Identifying those genes may shed new light on possible ways to enhance myelin repair in MS.
 

Tao Sun, PhD
Dana-Farber Cancer Institute
Boston, MA
Area: Central New England Chapter
Award: Advanced Postdoctoral Fellowship
Term: 7/1/01 - 6/30/04
Funding: $119,725

Regulation and function of gene expression in oligodendrocyte development

Examining the role of a specific protein in the formation of myelin-making cells, for clues to stimulating myelin repair in MS.

The destruction of myelin, the protective substance that insulates nerve fibers, is a progressive process in MS. Although myelin repair does occur in response to injury, it cannot keep up with the damage. Several studies have traced this ultimate failure of myelin repair to the supply of immature oligodendrocytes, the myelin-producing cells in the brain and spinal cord. When the supply of these immature oligodendrocytes, called progenitors, is depleted, myelin loss occurs and is not replaced. Oligodendrocyte genes are a critical element in the development of precursors.

Tao Sun, PhD, is examining the role of these genes in early oligodendrocyte formation, focusing particularly on how these genes are activated. He is also testing the genes’ effect on the development of immature oligodendrocytes. Answers to these important questions may help identify the precise conditions required to form oligodendrocytes capable of replacing those destroyed in MS. In so doing, they may also define new strategies to reverse the loss of myelin in people with MS.
 
 
 

20 New Pilot Grants Test Innovative Ideas

Over the last six months, 20 new grants were awarded through the Pilot Research Program.

These projects are aimed at quickly exploring new, untested ideas and generating preliminary data needed to apply for full grant support.
 

Central Nervous System Repair

Jeffery Kocsis, Ph.D.
Myelinating potential of transplanted bone marrow cells
Yale University, West Haven, CT,
$27,500;
04/01/01-03/31/02

Jacqueline Orian, Ph.D.
Is there a role for the growth factor, PDGF, in neuroprotective strategies for MS?
La Trobe University, Bundoora, Australia,
$25,000;
08/01/01-07/31/02
 

Neuropharmacology

Ulrich Bickel, M.D.
Novel drug therapy in MS: targeting the blood brain barrier with a transcription factor decoy
Texas Tech University Health Sciences Center, Amarillo, TX,
$27,500;
05/01/01-04/30/02
 

Rehabilitation

Alessandra Solari, M.D. “Controlled trial on the efficacy of computer-assisted cognitive rehabilitation in MS” National Neurological Institute Carlo Besta, Milan, Italy,
$22,500;
04/01/01-03/31/02

Scott Trappe, Ph.D. “Single muscle fiber structure and function in people with multiple sclerosis” Ball State University, Muncie, IN,
$27,500;
06/01/01-05/31/02
 

Psychosocial Aspects of MS

Robert Buchanan, Ph.D.
Nursing home residents with multiple sclerosis and depression
Texas A&M University, College Station, TX,
$27,500;
06/01/01-05/31/02

Herb Mathews, Ph.D.
Psychological and immunological impact of stress upon people with MS
Loyola University, Maywood, IL,
$27,500;
04/01/01-03/31/02

Robert Mendoza, Psy.D.
Development of an instrument in staff attributions of people with MS in long-term care settings
The Boston Home, Dorchester, MA,
$27,500;
06/01/01-05/31/02
 

Biology of Glial Cells/Myelin

Joseph Eichberg, Ph.D.
Modulatory role of tyrosine phosphorylation in myelin assembly
University of Houston, Houston, TX,
$27,500;
09/01/01-08/31/02

Joseph Neary, Ph.D.
Role of ATP and purinergic receptors in multiple sclerosis
University of Miami, Miami, FL,
$27,500;
06/01/01-05/31/02

Akiko Nishiyama, M.D., Ph.D.
A genetic approach to investigate oligodendrocyte differentiation
University of Connecticut, Storrs Mansfield, CT,
$27,500;
06/01/01-05/31/02

Jonathan Song, Ph.D.
In vivo functional assay of oligodendrocyte surface epitopes in the CNS
University of Wisconsin-Madison, Madison, WI,
$27,500;
05/01/01-04/30/02
 

Immunology

Yuan Chou, M.D., Ph.D.
Immortalization of neuropeptide-specific T cell clones in MS
Oregon Health Sciences University, Portland, OR,
$27,500;
05/01/01-04/30/02

Douglas Feinstein, Ph.D.
Suppression of EAE by peroxisome proliferator activated receptor-gamma ligands
University of Illinois at Chicago, Chicago, IL,
$27,500;
05/01/01-04/30/02

David Hafler, M.D.
Regulatory T cells in multiple sclerosis
Brigham and Women’s Hospital, Boston, MA,
$27,500;
06/01/01-05/30/02

Hugo Moser, M.D.
Antibodies to gangliosides that contain very long fatty acids
Kennedy Krieger Research Institute, Baltimore, MD,
$27,500;
04/01/01-03/31/02

Anthony Reder, M.D.
Study of IL-10 production in MS immune cells
University of Chicago, Chicago, IL,
$27,500;
08/01/01-07/31/02

Arlene Sharpe, M.D., Ph.D.
Role of Ox40L costimulation in induction and regulation of EAE
Brigham and Women’s Hospital, Boston, MA,
$27,500;
05/01/01-04/30/02
 

Infectious Triggers

Thomas Backstrom, Ph.D.
Modulation of the initiation and progression of MS by a Th2-response infection
Malaghan Institute of Medical Research, Wellington, New Zealand,
$25,000;
07/01/01-06/30/02
 

Biochemistry/Biophysics

Nephi Stella, Ph.D.
Effects of cannabinoids on microglial cell migration
University of Washington, Seattle, WA,
$27,500;
05/01/01-04/30/02
 

MS Tissue Banks: Precious Resources

The National MS Society recently renewed two long-time grants to support two important resources for the research community: MS tissue banks. Tissue banks are very close to what they sound like: areas set aside in laboratories or medical centers where tissue specimens are “deposited” and stored for later “withdrawal” and use. At the two long-standing MS tissue banks listed below, brain and spinal cord tissues, spinal fluid and other specimens from persons who had MS during their lifetimes are frozen or otherwise preserved very soon after death. Specimens from healthy individuals are also banked for comparison. The banked tissues are carefully catalogued with information about the donor’s medical history. This ready and crucial resource is available to any legitimate investigator seeking clues to the cause of multiple sclerosis.

Individuals with MS who are interested in supporting this important effort by becoming tissue donors can enroll (prior to death) by contacting the Society-funded centers below by phone or letter. Provided arrangements are made in advance, the banks can accept tissues from individuals from most parts of the U.S. The banks are also particularly interested in obtaining tissues from individuals nearby.

The decision to participate as a donor in this special type of research program is most thoughtful, and is truly appreciated by all who are involved in the effort to end the devastating effects of MS.

Rocky Mountain MS Center Tissue Bank
701 East Hampden Avenue
Englewood, CO 80110
1-303-788-4806
Website: http://www.mscenter.org/guide_tissue.htm

Human Brain and Spinal Fluid Resource Center
Veteran Administration Medical Center
11301 Wilshire Boulevard
Los Angeles, CA 90073
1-310-268-3536
Website: http://www.loni.ucla.edu/~nnrsb/NNRSB/
 

Nerve-Pathology Scientist Wins Dystel Prize

John W. Prineas, MB, BS, FRCP, was chosen by a committee of his peers to receive the 2001 John Jay Dystel Prize for Multiple Sclerosis Research. He is Professor of Neurology in the Department of Medicine at the University of Sydney’s Institute of Clinical Neurosciences.

Dr. Prineas defined the pathology of MS with pathbreaking research papers that are now standard references. In 1978, he published a landmark paper showing evidence that myelin, the insulating material that speeds nerve signals, is repaired in MS lesions (damaged areas). He was the first to describe – in the early 1980s – how brain and spinal cord myelin is destroyed in MS, and in 1993, he demonstrated that myelin repair can normally occur in MS, unless interrupted by disease activity. Dr. Prineas also was first to demonstrate the ability of myelin-making cells to regenerate in MS.

The $7,500 Dystel prize is given jointly by the National MS Society and the American Academy of Neurology, and is funded through the Society’s John Dystel Multiple Sclerosis Research Fund. Society National Board of Directors member Oscar Dystel and his wife Marion established this fund in honor of their son John Jay Dystel, an attorney whose promising career was cut short by progressive disability from MS.
 

“New Research” is produced twice a year by the National Multiple Sclerosis Society, Research Programs, 733 Third Avenue, NY, NY 10017-3288. For more information about multiple sclerosis research, call: 1-800-FIGHT MS or visit our Website: http://www.nationalmsssociety.org.

Visit the Research section of the Society’s Web site for the latest research news, ongoing clinical trials, and progress of Society-funded grantees:
http://www.nationalmssociety.org/research.asp.