Collaborative MS Research Center Award
Collaborative MS Research Center Award Skirball Institute,
James L. Salzer, MD, PhD,
New York University, New York, NY
Michael Dustin, PhD
Wenbiao Gan, PhD
Alexandra Joyner, PhD
Juan Lafaille, PhD
Summary: Investigating mechanisms that are critical for the initial events of immune-mediated myelin damage in MS and clarifying the sources of cells that might repair such damage to rebuild the nervous system.
Details: Multiple sclerosis results when the immune system attacks nerve fiber-insulating myelin sheaths in the brain and spinal cord. Loss of myelin, in turn, leads to nerve impulse conduction block and the progressive loss of associated nerve fibers.
The mechanisms that initiate the immune-mediated damage to myelin sheaths in this disease are poorly understood. Research indicates that certain brain cells, known as microglia and astrocytes, contribute to the initiation of nerve tissue damage. Therapeutic approaches that interrupt the inflammatory cascade therefore provide an important strategy to block this damage. An additional therapeutic goal is to enhance myelin repair, which is normally quite limited in MS, but is likely to restore nerve impulse conduction and prevent nerve fiber loss. Stems cells exist in the brain that might help to repair myelin, but these cells are somehow stifled by MS.
James L. Salzer, MD, PhD, has formed a collaboration to elucidate fundamental events in the development of myelin damage and also identify sources of stem cells for use in strategies to promote myelin repair. Dr. Salzer brings to this project a wealth of expertise in the complex process of myelin formation, and how this process may go awry in MS. The goal of this Center is to foster a cross-disciplinary team of researchers \with individual expertise in myelin, immunology, and neurobiology, and focus on unsolved questions surrounding MS.
Collaborator Juan Lafaille, PhD, has been a pioneer in understanding the role of regulatory T cells in EAE, an MS-like disease. T cells are major players in the immune attack in MS, and thus, the mechanisms that regulate the trafficking of T cells into the brain and spinal cord provide an important opportunity for therapeutic intervention. Signals from immune messenger proteins known as “chemokines” have recently been
identified as crucial for recruiting T cells to the brain. Dr. Lafaille is joining with Michael Dustin, PhD, a leader in imaging the trafficking of immune cells. They have recently developed methods for imaging T cell migration and activation in the living spinal cord in animal models, and are now using these methods to study specific chemokines and their involvement in the immune attack in EAE models developed by Dr. Lafaille.
In other experiments, Dr. Lafaille is joining forces with Wenbiao Gan, PhD, who has pioneered methods for live imaging of microglia in the brain and spinal cord. They are now using these methods to determine whether these brain cells respond very early to the immune attack in EAE, whether this response boosts recruitment of T cells, and whether it results in damage to nerve fiber themselves. Microglial activity is reduced using drugs known as NSAIDs (non-steroidal anti-inflammatory drugs), so Drs. Lafaille and Gan are administering these drugs to mice to determine whether decreasing the effects of microglia can reduce T cell infiltration and nerve fiber damage in EAE. Dr.Gan is new to the field of MS research.
Finally, Dr. Salzer is working on myelin repair strategies with Alexandra Joyner, PhD, an expert in brain development, who also is new to MS research. Dr. Joyner has developed a mouse model in which stem cells resident in the brain respond to a protein known as “sonic hedgehog” to develop into astrocytes, nerve cells, and oligodendrocytes (myelin-making cells). To test whether these stem cells are an important source of oligodendrocytes that can stimulate myelin repair in MS, Drs. Salzer and Joyner are inducing myelin damage in these mice. If they prove to be an important source of remyelinating cells, they will examine the role of these cells in the EAE models developed by Dr. Lafaille.
These studies are expected to provide important new insights into basic mechanisms that are critical for the initial events of immune-mediated myelin damage and clarify the source of cells that might repair such damage. In the future, these new insights will serve as a foundation for translational studies directed at the treatment of MS.