Determining the Mechanisms Underlying Remyelination by Surviving Oligodendrocytes
Abstract
Rationale and Objective: Myelin, the electrical insulation around neuronal axons, enables rapid information transmission across the nervous system. In multiple sclerosis, the immune system destroys myelin, causing demyelination of axons and leading to motor, sensory, and cognitive impairment. Creating new myelin, also known as remyelination, is the primary means for restoring function. However, remyelination that occurs naturally in patients is often limited, leading to disease progression in many people with multiple sclerosis. New strategies to increase remyelination are necessary to improve functional recovery in patients. Prior approaches to enhance remyelination have focused exclusively on increasing the formation of new oligodendrocytes, the cells that make myelin. However, recent findings from our laboratory and others have demonstrated that remyelination also occurs through other means. These studies found that oligodendrocytes that survive demyelination can also participate in remyelination, making new myelin sheaths to remyelinate axons. Enhancing the capacity of surviving oligodendrocytes to remyelinate axons could be a successful strategy to increase remyelination and functional recovery, especially considering that new oligodendrocyte formation is often inhibited in multiple sclerosis. Critically, we do not yet understand the molecular mechanisms regulating the capacity of surviving oligodendrocytes to remyelinate. Thus, I propose to investigate these mechanisms. I hypothesize that surviving oligodendrocytes increase the expression of genes that are typically involved in myelin formation by new oligodendrocytes. Additionally, I hypothesize that the gene Fyn, which is known to promote myelin formation by new oligodendrocytes, enables surviving oligodendrocytes to form new myelin. FY22 MSRP Focus Area: This project directly addresses the Central Nervous System Regenerative Potential in Demyelinating Conditions FY22 MSRP Focus Area. This Focus Area outlines the need for scientific studies that identify new factors that promote myelin repair. By elucidating the molecular mechanisms regulating the capacity of surviving oligodendrocytes to remyelinate, this study will identify new factors involved in myelin repair. Advancing Multiple Sclerosis Patient Care: Understanding the molecular mechanisms mediating surviving oligodendrocyte remyelination is the critical first step toward enhancing this myelin repair pathway in patients. Future work will test drugs known to target this molecular mechanism for their ability to increase the remyelinating capacity of surviving oligodendrocytes. This work would commence immediately following the identification the molecular mechanisms mediating surviving oligodendrocyte remyelination and could result in the identification of new drugs to increase remyelination efficiency and restore function in multiple sclerosis patients. Recent evidence from multiple sclerosis patients indicates that surviving oligodendrocytes are present in regions of previous demyelination known as shadow plaques. A drug that enhances remyelination by surviving oligodendrocytes could be administered to patients at all stages of progression to improve remyelination of shadow plaques or of future demyelinating lesions.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310561
Entities
People
- Lindsay Osso
Organizations
- United States Army
- University of Colorado Denver