Collaborative MS Research Center Award
$816,750; 4/1/05-3/31/10
Principal Investigator
Lawrence Steinman, MD
Stanford University, Palo Alto, Calif.
Collaborators
P. J. Utz, MD
William Robinson, MD, PhD
Ajay Chawla, MD, PhD
Stanford University
Purpose
Using novel technology to study the immune attack in MS on a broad scale to identify targets for therapies aimed at specific components of this attack.
Summary
New techniques in molecular biology allow researchers to study the components that cause or may help cure diseases on an unprecedented scale. This is especially valuable in a complex disease such as multiple sclerosis, where many cells and molecules participate in the immune attack on the brain and spinal cord, presenting many targets for therapeutic strategies.
Lawrence Steinman, PhD, is a pioneer in this area of MS research. Dr. Steinman was honored with the 2004 National MS Society/American Academy of Neurology's 2004 John Dystel Prize for Multiple Sclerosis Research, for his major contributions to our understanding of MS-like disease models, and for translating these findings to the clinical development of novel therapeutic strategies for MS.
Dr. Steinman's team recently performed a large-scale analysis of genes in brain lesions—areas of inflammation and tissue damage—from people with MS. Such analyses can point to enzymes, proteins, and other molecules in MS lesions that might be related to the disease cause and severity.
Now, together with P.J. Utz, MD, and William Robinson, MD, PhD—colleagues with expertise in the molecular and chemical aspects of autoimmune disease—Dr. Steinman is exploring the immune cells, antibodies and messenger proteins involved in the immune response against nerve-fiber insulating myelin in MS. Although myelin proteins are well studied, this team also is studying other myelin components such as lipids (fat-like molecules) and carbohydrates. They are using advanced forms of microarray technology that were developed by Drs. Utz and Robinson, in collaboration with Dr. Steinman. This technology employs highly specific electronic sensors that can detect clinically important molecules associated with human autoimmune diseases. The group also will test their results in blood samples from participants involved in clinical trials of several experimental agents under study for MS, to determine how these agents affect the molecules identified.
This center is helping to advance therapies for MS in other ways. Joining the team is Ajay Chawla, MD, PhD, an accomplished molecular endocrinologist who has focused primarily on the role of PPAR agonists—molecules that appear to have important roles in modulating inflammation as well as in the growth and proliferation of immune cells. These drugs have been used to treat cholesterol disorders, Dr. Chawla's area of expertise. He is now applying this expertise to help the center determine the applicability of these drugs for MS in rodent models and human studies.
Recent Progress
The team recently reported on a specific modulator of the immune response that is triggered by both fatlike molecules and sex hormones, known as peroxisome proliferation activated receptor (PPAR). They hypothesized that this gene may mediate sex differences in the development of MS-like disease in mice. The results showed that one PPAR molecule found on T cells, PPAR-alpha, is more abundant in male as compared with female mice. Deleting the gene for this molecule caused male, but not female, mice to develop more severe MS-like disease. These results suggest that males are less prone to develop this disease because PPAR-alpha is more active on their immune cells.