Probing Oligodendrocyte Lineage Cell Autocrine Signals to Treat Multiple Sclerosis
Abstract
Objectives and Rationale: Neurons in the brain form neural circuits by connecting with one another with long and thin axons similar to electric wires. Oligodendrocyte-lineage cells (OLCs) form myelin that wraps around axons similar to insulating plastic covers of electric wires. Myelin is essential for the function of axons and the electrical communications within neural circuits. In multiple sclerosis (MS), the immune system attacks myelin, leading to myelin and axon damage, and loss of the abilities to walk, talk, see, and remember. Currently available MS treatments can reduce immune attacks of myelin, thus slowing down the deterioration of symptoms. However, these treatments cannot repair damaged myelin or axons and most patients on these treatments eventually deteriorate as the disease progresses. To develop new treatments aimed at repairing damaged myelin and curing MS, scientists need to know what signals stimulate OLCs to form new myelin. In the past several decades, scientists have made great progress in understanding signals that work inside individual OLCs, However, whether OLCs communicate with one another and whether their communication stimulates the formation of new myelin are unclear. Progress in studying OLC communication has been slow in the past several decades because signal molecules from OLCs and other types of cells in the brain are mixed and thus hard to decipher. In pilot studies, we developed a new technology to block communication only between OLCs. This technology is similar to creating the mute button in a Zoom meeting, allowing us to mute one participant in a Zoom meeting to observe what happens when this participant is not allowed to communicate. This selective mute technology thus allows us to understand the contribution of this participant to the accomplishment of the group. When we applied our new method to mute OLC communications in mice, we found that OLCs form less myelin and the mice suffer from movement problems. This interesting discovery suggests that OLCs produce signals that encourage themselves and other OLCs to make new myelin, similar to people in a community that encourage one another to work for a common cause. We reasoned that we could use this encouragement signal to stimulate new myelin formation in MS patients. In this proposed study, we will exploit the OLC-to-OLC encouragement signal to promote brain repair. In Specific Aim 1, we will apply our new method to mute OLC communication in a mouse model of MS and identify the involvement of OLC communication in the formation of new myelin after myelin loss and the recovery of motor function. In Specific Aim 2, we will generate a catalog of the communication signals used by OLCs. We will next identify which communication signal molecule(s) can promote OLC growth and myelin repair. Focus Area: Central nervous system regenerative potential in demyelinating conditions. We will identify cell-cell interactions and factors that promote remyelination and functional recovery. The Applicability of the Research to Advance MS Patient Care: Recent data from clinical trials suggest that it is possible to improve the neurological function and the quality of life of MS patients by stimulating new myelin formation even after myelin has been lost for a long time. However, no large-scale clinical trial that stimulates new myelin formation has been successful so far, highlighting the need to identify novel ways to stimulate new myelin formation. In contrast to previous studies that target myelin-promoting signals working inside individual OLCs, our study will target OLC-to-OLC communication and discover myelin-promoting signals that work outside of OLCs. Our approach holds promise for discovering a novel group of myelin-promoting molecules that have not been previously tested and may lead to a new category of MS therapies. Results from this study can be immediately translated into clinical trials. If
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310387
Entities
People
- Ye Zhang
Organizations
- United States Army
- University of California, Los Angeles