Role of m6A mRNA Methylation in CNS Remyelination and Inflammation
Abstract
Background: Multiple sclerosis (MS) is a chronic debilitating disease, caused by the accumulation of inflammatory cells and myelin damage, a fatty substance that is essential for proper neuronal signaling and function. Cells in the central nervous system (CNS) (brain and spinal cord) that produce myelin are called oligodendrocytes. Following insults to the CNS that result in the loss of myelin (demyelination), these cells have the capacity to produce myelin again, a process called remyelination. However, these cells are highly sensitive to the inflammatory attacks that occur in MS patients. A number of symptoms are caused by the loss of these cells and the myelin that they produce. These symptoms include numbness and/or paralysis, blindness, slurred speech, as well as cognitive dysfunction (during later disease stages). Although current MS treatments can help manage these symptoms by dampening the inflammatory attacks, they have limited impact on inhibiting MS progression. Researchers have been working to understand various biological mechanisms so the survival of myelin-producing cells and their capacity to produce new myelin can be enhanced. Recent studies discovered a biological mechanism called mRNA methylation that influences the development and maintenance of cells. Based on our previous work, we believe mRNA methylation could play a critical role in the survival of myelin-producing cells and their capacity to produce new myelin. Therefore, in the current proposal we will try to understand if mRNA methylation has a role in myelin-producing cells to enhance the capacity of remyelination. Further studies will be dedicated to examining the role of mRNA methylation in the response of myelin-producing cells to inflammation. Protection of these myelin-producing cells will allow for the preservation of myelin production, maintenance and remyelination, and thus will be highly beneficial to effectively alleviate the symptoms and reduce disease severity. Objectives and Rationale: Our previous studies have shown that mRNA methylation is critical in the development of myelin-producing oligodendrocyte cells. However, whether this mechanism plays a role in the protection of myelin-producing oligodendrocyte cells in MS disease is unclear. Therefore, the proposed project s aims are to (1) study the role of mRNA methylation in the CNS remyelination process. In this aim, our studies will focus on evaluating the role of mRNA methylation on the development of myelin-producing oligodendrocyte cells in response to demyelination. Further, we will investigate the impact of mRNA methylation in the CNS remyelination process using a mouse model with MS-like symptoms. Further studies will be dedicated to (2) exploring the role of mRNA methylation in protecting myelin-producing oligodendrocyte cells from an inflammatory environment (similar to that which occurs in MS). This study will provide useful information on whether the survival of these cells can be enhanced against inflammation. Overall, outcomes from these studies might help to discover novel pathways/targets as a new treatment for MS which can be also further studied. Impact of the study?for people affected by multiple sclerosis: We anticipate that the information gained from this study will eventually initiate novel MS therapies that provide direct protection to myelin and myelin producing oligodendrocytes in the CNS. In combination with current treatments, we believe that a cell-specific treatment would likely have significant therapeutic benefits for alleviating MS relapses and preventing disease progression. If the research is successful, these potential results could come to fruition within 3-5 years. In addition, currently there are no proper biomarkers available for early detection of MS. Therefore, if this research is successful in demonstrating whether changes in mRNA methylation levels in CNS cells can cause malfunction in their ability to re
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310537
Entities
People
- Vaibhav Patil
Organizations
- Northwestern University
- United States Army