Collaborative MS Research Center Award
$767,251; 4/1/08-3/31/13
Principal Investigator
Jenny P-Y Ting, PhD
Co-Investigators
Albert S. Baldwin, PhD
Manzoor A. Bhat, PhD
Silva Markovic-Plese, MD
Glenn Matsushima, PhD
Purpose
Basic and clinical researchers exploring steps leading to injury to the central nervous system in MS and new strategies to stop the disease.
Details
Ideally, our immune system functions to protect us from dangerous substances. In the case of multiple sclerosis, however, the immune response mistakenly targets the brain and spinal cord, damaging the myelin insulation of nerve fibers. Nerve fibers are damaged as well. “T cells” are a major player in the immune response, so therapeutic strategies that could prevent activation of T cells would be key to treating and possibly preventing MS.
Jenny Ting, PhD, and colleagues recently identified molecules involved in activating T cells that may be prospective therapeutic targets for stopping MS in its tracks. These molecules are “Plxna1,” which exists on the surface of dendritic cells — immune cells that present substances to T cells — and “Sema6D,” a docking site for Plxna1 on T cells.
Now Dr. Ting — who is nationally recognized for numerous contributions to MS research — has gathered a team of MS research colleagues, and has recruited experts from other fields, to study these exciting findings further and bring them closer to use as a therapeutic strategy for MS.
In one project, Dr. Ting is examining the activity of Sema6D on T cells derived from people with MS. She is working with Silva Markovic-Plese, head of the MS clinic at the university, and Manzoor Bhat, PhD, an expert in interactions between myelin-making cells and nerve cells, and who is new to MS research. This group is exploring if inhibitors of Sema6D will reduce the proliferation of disease-causing T cells in lab culture dishes. They also are exploring, with Dr. Bhat’s expertise, whether Sema6D on T cells also interacts with Plxna1 molecules that are found on nerve cells and myelin-making cells.
This group is joined by Glenn Matsushima, PhD — a longtime MS researcher who has uncovered the function of several important molecules affecting the immune response — in another project. One of Dr. Ting’s seminal contributions to MS research was the discovery of MHCII in the brain, a set of proteins that are expressed on the surface of the brain’s resident immune cell, microglia. These proteins serve as “tags” that T cells respond to when launching the immune attack.
However, MHCII also is important in rodent models of MS-like disease that do not involve T cells, indicating that MHCII may have another function in MS. Dr. Matsushima is now studying a novel molecule, LAG3, that binds to MHCII and is increased in immature myelin-making cells. He is helping the team determine whether communication between microglia and these immature cells is important to the immune attack in MS and possible therapeutic strategies. They are examining LAG3 activity in areas of myelin damage from mice and in brain tissue of people with MS.
In another project, the team is using novel technology to screen so-called “libraries” containing thousands of proteins that may trigger T cells. They are specifically looking at which proteins trigger immune cells isolated from people with active MS to respond.
Another investigator new to MS, Albert Baldwin, PhD, is bringing a wealth of experience in studying a potential troublemaker in the immune attack in MS — “NfkappaB.” This is a transcription factor, a molecule that can impact genes in the immune system, such as those that produce immune messenger proteins that help T cells recruit soldiers for the attack in MS. Dr. Baldwin’s lab has devised a method of inhibiting the NFkappaB pathway, and is helping Dr. Ting’s team to investigate the therapeutic potential of this approach in models of MS-like disease.
Dr. Bhat is also investigating interactions between myelin-making cells and nerve cells in MS-like disease in rodent models, and how this interaction leads to nerve fiber damage. These studies are crucial to figuring out how to stop MS progression.
This talented group, focusing its expertise on a variety of strategies, should make great strides in our understanding of both the early immune attack and chronic damage to nervous system tissue in MS, yielding potential targets for new treatment approaches.