Targeting Circadian Control of Oligodendrocyte Lineage Cell Dynamics for Remyelination
Abstract
The aim of this proposal is to address FY20 Multiple Sclerosis Research Program (MSRP) Investigator-Initiated Research Award Focus Area Central Nervous System Regenerative Potential in Demyelinating Conditions, supporting innovative mechanistic studies to promote remyelination in a relevant experimental model of demyelination (lysolecithin-induced demyelination). This includes obstacles to repair and approaches to overcome and achieve remyelination, specifically related to novel intrinsic circadian regulation of myelin-forming cells. Myelin, the multi-layered structure that surrounds and insulates neuronal axons, allows for efficient communication between neurons. Nearly half of the human brain is composed of white matter tracts that consist of these myelinated axons in which new myelin-forming oligodendrocyte production from the oligodendrocyte precursor cell (OPC) population is critical to neurodevelopment, maintenance, and plasticity. The OPC is the most consistently cycling cell in the brain, yet the processes that mediate this robustness remain unknown. One mechanism known to strongly moderate the cell cycle is the circadian or 24-hour clock. At the cellular level, 24-hour rhythms are generated by a genetic negative feedback loop driven by the transcription factors BMAL1 and CLOCK. The proteins BMAL1 and CLOCK bind together and initiate the transcription of the Period and Cryptochrome family of genes, whose protein products feed back and block BMAL1. This loop takes approximately 24 hours, resulting in the generation of circadian rhythms at the cellular level. Protein products from this 24-hour molecular clock also regulate the cell cycle. Virtually every cell in the brain and body, including OPCs, cycles on an approximate 24-hour schedule, which when synchronized to each other and to the external environment by the brain s master clock, the suprachiasmatic nucleus, allows for entire organ systems, and thus organisms, to adhere to the 24-hour light/dark cycles experienced on Earth. Despite the known importance of the circadian system in neuronal and peripheral cell maintenance, the role it plays in modulation of the myelin-forming cell population remains unstudied, leaving a significant gap in our understanding of myelination. Multiple sclerosis is an autoimmune disorder afflicting over 1 million people in the United States alone. It is a progressive neurological disorder in which the underlying etiology involves the attacking and degradation of myelin by the body s immune system, leading to deficits in vision, coordination, muscle movement, tremors, pain, and fatigue. The majority of patients with MS report sleep abnormalities associated with altered circadian rhythms. The incidence of MS significantly increases in individuals who participate in circadian-disruptive shift work prior to 20 years old. The impact of temporal disruptions on the pathophysiology of MS is further underscored by the finding that MS increases in prevalence with increasing distance from the equator. One of the many changes that accompany geographic latitudes approaching the poles is variations in the light/dark cycle with substantial portions of the year experiencing light cycles ranging from continual light to continual darkness, two lighting environments known to disrupt circadian rhythms. Additionally, genetic variability in Bmal1, Clock, and Per3 are associated with elevated risk of MS. These findings suggest disruptions in circadian biology are associated with MS. One unfortunate side-effect of modern 24-hour electricity is a dramatic increase in temporal disruptions in human populations. Transmeridian travel, shift work, dim-light-at-night, and sleep disturbances plague modern society. How this constant desynchrony between our internal circadian clocks and external timing cues impacts brain structure and function remains incompletely understood. In the present proposal, we aim to elevate the current biological
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110846
Entities
People
- Erin Valdez
Organizations
- Stanford University
- United States Army