Published March 28, 2018 This content is archived.
Research led by Fraser J. Sim, PhD, associate professor of pharmacology and toxicology, that seeks to spur development of cellular and molecular therapies for adult demyelinating disease, such as multiple sclerosis, has gained funding from the National Institutes of Health.
In multiple sclerosis, impaired oligodendrocyte differentiation limits remyelination and leads to axonal atrophy and neurodegeneration, according to Sim, principal investigator on the grant.
“Drugs which block muscarinic receptors (MR) have been shown by us and others to improve remyelination and myelin repair in rodents,” he says.
“Understanding the mechanisms by which these drugs act and the role of muscarinic acetylcholine (ACh) signaling in oligodendrocyte progenitor cells (OPCs) is of paramount importance to the successful clinical translation of this approach.”
Sim notes the development of cellular and molecular therapies to treat developmental leukodystrophy and adult demyelinating disease, such as multiple sclerosis, have been hampered by a lack of understanding of human oligodendroglial development and regulation.
“We will help address these needs by studying the function and mechanisms-of-action of muscarinic type 3 receptor (M3R) in models of human transplant-mediated repair and spontaneous remyelination,” he says.
“The results of these experiments are expected to lead to the definition and characterization of novel therapeutic targets for the treatment of demyelinating disease.”
In 2015-2016, Sim received pilot study funding from UB’s Clinical and Translational Science Institute to test genetic approaches to specifically delete and impair M3R signaling for their effects on oligodendrocyte differentiation and remyelination.
“Importantly, our preliminary studies provide direct evidence for a role of M3R function in human and rodent OPC differentiation,” he says.
“However, the mechanism by which MR signaling blocks differentiation is poorly understood as well as the sources of ACh that become active in demyelinating disease.”
Sim says the new study addresses these gaps using both human and rodent cells and a variety of animal models to maximize the chances for future therapeutic development.
“Our project will establish the therapeutic utility of specifically targeting M3R to improve myelin repair, the mechanisms by which M3R acts to block OPC differentiation, and the functional sources of ACh during remyelination,” he says.
“In addition to the now-established role of activity-dependent differentiation and myelination, these studies will begin to characterize the novel concept that some neurotransmitters such as ACh act to prevent untimely OPC differentiation.”
The five-year study, titled “Muscarinic Receptor Type 3 Regulation of Oligodendrocyte Progenitor Differentiation,” has received $1.7 million in funding from the National Institute of Neurological Disorders and Stroke.
Richard J. Salvi, PhD, SUNY Distinguished Professor, is a co-investigator from the Department of Communicative Disorders and Sciences.