Each year multiple sclerosis (MS) strikes millions of young adults in the United States and worldwide, limiting their mobility, causing disability and pain, and seriously affecting their quality of life. Onset is observed in young adults in their 20's and 30's, with a pediatric form of MS becoming increasingly prevalent. While various current treatments delay progression or manage the symptoms, there is currently no cure and there is significant decline over a 15-20 year period with a large number of patients progressing from a relapsing remitting disease course to a progressive disease course.
For over 30 years, Einstein Pathology researcher Bridget Shafit-Zagardo, PhD, has worked to understand MS and give people suffering from the neurological disease hope.
“We’re predominantly interested in enhancing repair and functional recovery following central nervous system (CNS) injury,” said Dr. Shafit-Zagardo, a professor of pathology, who joined Einstein in 1984.
She explained that MS damages neurons, or nerve cells, and the myelin sheath - the insulation that surrounds and protects axons. The loss of myelin – demyelination - interferes with the transmission of normal nerve conductance required for nerves to signal between the brain, spinal cord and the rest of the body.
“The goal is to repair axonal damage and enhance remyelination,” she said, noting that the current treatments address inflammation, but do not address nerve cell repair.
The exact antigen — or target that the immune cells are sensitized to attack — remains unknown, which is why MS is considered by many experts to be "immune-mediated," she said.
Abnormally hyper-activated infiltrating immune cells cross the blood brain barrier and induce inflammation in the CNS. As a result, resident cells of the CNS become activated and secrete inflammatory molecules that further enhance inflammation resulting in damage to neurons and oligodendrocytes, the myelin-synthesizing cells of the CNS. Axonal damage, destruction of myelin and activation of astrocytes called astrogliosis, ultimately result in CNS lesions referred to as glial scars or plaques in areas of damage. The resulting insult affects nerve fibers producing symptoms that may affect vision, coordination and mobility, and continence, among other symptoms.
To that end, Dr. Shafit-Zagardo and her team are investigating strategies to slow the progression of axonal damage and demyelination and to enhance remyelination.
“Until damaged myelin and cell debris resulting from inflammation are cleared, you do not have efficient repair and recovery cannot occur,” said Dr. Shafit-Zagardo. The lab’s ongoing projects include applying techniques of molecular & cell biology, biochemistry, immunocytochemistry, confocal and electron microscopy to address questions concerning the structure, function and regulation of myelination in the normal CNS and remyelination following neuroimmune injury.
Identifying signaling pathways
Central to the treatment of MS is how cell signaling pathways regulate oligodendrocyte cell survival and remyelination after the inflammatory response.
Toward this goal, the lab has used molecular approaches to identify several genes implicated in signaling pathways that regulate oligodendrocytes and protect against demyelination. Among those genes identified were members of the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases. As Dr. Shafit-Zagardo explained, to clear debris in MS lesions, the ligand or growth factor binds to receptors on the cell and signals downstream, recruiting signaling molecules that are protective for survival of the cell and also serve to activate other signaling pathways necessary for repair. The lab has demonstrated that signaling through the growth arrest-specific protein 6 (Gas6)/TAM pathway protects oligodendrocytes against injury.
Dr. Shafit-Zagardo’s research is funded by grants from the National Multiple Sclerosis Society and the National Institute of Neurological Disorders and Stroke. Assisting Dr. Shafit-Zagardo in her research is postdoctoral fellow Ross Gruber, graduate student Alex Ray and technician Kathleen O’Guin. Ross and Alex have been generating different mouse models, including single and double knockout mice that can be used to study different signaling pathways.
Despite her many achievements both inside and outside of science, the Bronx native has not had to venture far. After earning her master’s degree in biology at New York University, she studied human genetics with Dr. Robert Desnick and was awarded a PhD from City University of New York/ Mount Sinai School of Medicine, where her research focused on lysosomal storage diseases focusing on Gaucher’s disease. She initially joined Einstein as a postdoctoral research fellow under the mentorship of Dr. Joseph Maio in Cell Biology, working on long interspersed repetitive sequences. Dr. Shafit-Zagardo became involved in MS after seeing that early developmental genes could be turned back on during remyelination, and continued to expand on those initial studies.
MS research has come a long way in the last two decades. “Thirty years ago, there were no real treatments,” Dr. Shafit-Zagardo said, noting that the last 20 years has seen a variety of medications used for MS to block inflammation, but they do not target myelin repair.
Moving forward, her lab will continue to work toward developing better treatment and attempt to attempt to find factors that can aid in repair. She said, “Once we’ve determined how signaling occurs we will be able to use this information to protect against further damage."