Collaborative MS Research Center Award
Collaborative MS Research Center Award Skirball Institute,
Joel M. Levine, PhD,
SUNY, Stony Brook, NY
Styliani-Anna E. Tsirka, PhD
Holly Colognato, PhD
Mirjana Maletic-Savatic, MD, PhD
William E. Van Nostrand, PhD
SUNY, Stony Brook, NY
Aim: Characterize resident cells in the brain capable of repairing myelin and develop techniques and molecules to induce them to rebuild damaged tissues in MS and restore function.
Details: Multiple sclerosis is characterized by repeated, immune-mediated attacks that damages nerve fiber-insulating myelin in the brain and spinal cord. MS usually progresses from an episodic, inflammatory disease to a chronic, progressive disease. During the early phase, areas of myelin damage (also known as lesions) are repaired, but repair fails during the chronic phase despite the presence of immature myelin-making cells (oligodendrocyte precursor cells, or OPCs) within chronic lesions. This suggests that certain factors limit the ability of OPCs to promote repair in people with MS.
Joel M. Levine, PhD, has brought together a cadre of established investigators to focus their collective expertise on characterizing these cells and developing techniques for modulating them to induce repair in MS. These investigators share a common goal of understanding the environment of the brain and spinal cord in MS. Each laboratory has equipment, expertise, and diagnostic techniques that are unique to their individual projects.
Dr. Levine has a strong research program that investigates OPCs using a mouse model that lacks NG2, a molecule found on the surface of these cells whose activity is increased if myelin damage is induced. He is now determining whether NG2 functions in OPC migration and differentiation, by studying OPCs from this mouse model; if they migrate poorly or fail to differentiate into oligodendrocytes, this will indicate that NG2 is required for proper repair of myelin damage.
Styliani-Anna E. Tsirka, PhD, is studying the role of the immune attack on myelin damage and nerve fiber loss, in particular, tissue plasminogen activator (tPA, which is upregulated in the brains of MS patients), microglia (brain cells active in the immune attack) and nitric oxide (a molecule that may activate microglia). Dr. Tsirka is using models lacking these cells/molecules for examining cell migration and differentiation after myelin damage is induced. Understanding the specific pathways by which the immune attack affects OPCs can help develop treatments for MS that do not require widespread immunosuppression.
William Van Nostrand, PhD, studies myelin basic protein (MBP), a major component of myelin. A novel hypothesis suggests MBP may function as an enzyme that degrades itself. Dr. Van Nostrand is examining the possibility that another class of proteins normally found in the brain protease inhibitors may help to prevent MBP from degrading itself. He is studying mice that are genetically engineered to have too much or too little of these proteases. Dr. Van Nostrand directs an active basic research program in biochemistry and molecular pathology, and is relatively new to MS research.
Holly Colognato, PhD, is a Career Transition Fellow of the National MS Society. Her lab is investigating how external signals to OPCs may go awry in MS. For example, Dr. Colognato is studying one protein called laminin, which is found on the surface of nerve cells and stimulates oligodendrocytes to produce myelin during early development. She is studying the effects that faulty laminin signaling may have on myelin growth.
Mirjana Maletic-Savatic, MD, PhD, new to MS, has extensive expertise in imaging. Her investigations primarily involve visualizing neural stem cell (NSC) interactions. There is evidence that these cells may have therapeutic value in MS, but cell survival is difficult to maintain in transplants in animal models. Many factors might be responsible for accepting transplanted NSCs in the nervous system, including cells such as OPCs. Dr. Maletic-Savatic is studying the interactions of NSCs and OPCs using multiphoton microscopy, a technology that allows for observation of living cells and tissues at extremely high resolution.
Dr. Maletic-Savetic also is translating these neuroimaging studies from mouse models to people with MS. In this effort, Dr. Levine’s center will be able to draw from the clinical expertise of advisor Lauren Krupp, MD, director of the National Pediatric MS Center at SUNY Stony Brook, and Patricia Coyle, MD, chairman of the department of neurology.
These investigators are combining extensive expertise in their own field of interest in order to better understand the complex interactions that prevent spontaneous repair in MS. This understanding is a prerequisite to developing cell transplantation strategies to promote this repair in people with MS.