A Novel Signaling Pathway to Promote Oligodendrocyte Maturation Leading to a New Treatment for Multiple Sclerosis
Abstract
Focus Area: Central Nervous System Regenerative Potential in Demyelinating Conditions In multiple sclerosis, the protective myelin sheath around neurons in the brain degenerates. This protective sheath is provided by specialized cells called oligodendrocytes. The healthy brain normally has a mechanism in place to produce new oligodendrocytes that can replace the protective sheaths if they are lost or damaged. To do so, the brain maintains a population of cells known as oligodendrocyte progenitor cells (OPCs). The brain has the ability to transform some of these OPCs into mature oligodendrocytes, which can then repair any lost myelin. How OPCs are instructed to mature into oligodendrocytes is poorly understood, but it is clear that this process is restricted or lost during multiple sclerosis disease progression, which includes progressively increasing symptoms and disability. This project endeavors to identify a previously unknown pathway by which the brain can be used to create new oligodendrocytes from its resident pool of OPCs, thus promoting myelination after demyelinating injury. This work will open the door to target this pathway and treat multiple sclerosis using a new approach to address the lack of myelin regeneration. We have discovered that a protein not previously associated with oligodendrocytes is made by OPCs, and we hypothesize that it initiates a signaling pathway leading to OPC maturation into oligodendrocytes. To test this hypothesis, we will use mice that we engineered to either lack the ability to make this protein or make an overabundance of it. After these mice are given drugs to cause demyelination, we expect that the amount of this protein made will determine the mouse s ability to recover from the demyelination: Mice not making this protein will remyelinate less and those with more of this protein will remyelinate more than control mice. In addition, we will study the effect of this protein on OPCs grown in culture dishes to biochemically dissect how this protein promotes oligodendrocyte maturation involved in demyelination recovery. Results from this study will contribute important new information on the science underlying the maturation of oligodendrocytes required for brain repair in patients with multiple sclerosis. Our studies will interrogate the function of this protein to promote the production of new oligodendrocytes, which would then be applied to the development of small molecule drug(s) designed to mimic the activity of this protein to promote brain repair. This research is agnostic about the initial causes of multiple sclerosis, and we expect this eventual treatment to be relevant to all multiple sclerosis patients, regardless of the initial cause. However, this proposed project is only about 1 year old, and is still at the stage of animal research. After the funding period of this proposal, we expect that the subsequent funding period will move this project to translational research designed specifically to identify novel treatments for multiple sclerosis patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110707
Entities
People
- David Martinelli
Organizations
- United States Army
- University of Connecticut Health Center