Investigation and Therapeutic Targeting of Metabolic Pathways in Microglia for Efficient Remyelination in MS
Abstract
My lab is interested in finding the cause of multiple sclerosis (MS) and is dedicated to finding a cure for its treatment. In MS, immune cells such as macrophages (immune cells that eat damaged cells and cause inflammation), T and B cells (other types of immune cells) reach the brain and damage the myelin. Myelin is a fatty material that wraps around the brain cells called neurons. The loss of myelin causes neurons to become less effective, causing MS symptoms such as difficulty in walking, blurred vision, etc. Microglia are the macrophages inside the brain that eat damaged myelin to remove them from the brain tissue. This is important because it allows the new myelin to be wrapped around neurons by oligodendrocytes, the myelin-making cells in the brain. Microglia use special energy (metabolism) that helps these cells to remove damaged myelin. But microglia become less effective in myelin removal during the long-term MS, and we believe it is due to the changes within microglia metabolism, details of which are not yet known. My lab is interested in finding this information for microglia so we can use drugs to help microglia recover their normal functions. In this grant, we propose to find and stop the disease-related metabolic changes in microglia. We believe that this strategy will help repair the lost myelin and reduce disease progression in MS brains. Basis of our hypothesis: Our earlier studies found that macrophages that travel from blood to the brain during MS depend on glucose metabolism (glycolysis). We also found that if we blocked glycolysis using dietary factors such as cinnamic acids, it reduced the disease in the mouse models of MS. Because microglia are the brain macrophages and promote MS progression (steady decrease in brain health), drugs that directly target microglia metabolism can be effective in treating the progressive forms of MS. Working on the ideas of Central Nervous System Regenerative Potential in Demyelinating Condition we have set the following short-term and long-term goals to achieve our objectives: 1. Short term goals (1-2 years): a. Using different mouse models of MS and human MS brain samples, we will study and recognize the energy needs of microglia in MS. b. We will test drugs that block disease-causing metabolic pathways within microglia to reduce inflammation and increase myelin removal by these cells. 2. Long-term goals (2-5 years): a. We will study changes within microglia in old mice to understand age-related changes in microglia functions. b. We will study how microglial metabolism directly affect oligodendrocytes for increasing their myelin-wrapping around neurons. c. We will build collaborations with basic and clinical researchers (local and international) to promote novel treatments such as replenishing compromised energy in non-functional microglia for patient use. We will test if dietary factors such as cinnamic acid will help restore the lost energy in microglia Patients benefitting from this approach: Because microglia are involved in early and progressive MS, we believe that our findings will benefit relapse-remitting MS patients as well as progressive MS patients. Risks and benefits: Existing MS drugs are known to target metabolism in different kinds of immune cells and have shown no side effects, so we are certain that targeting metabolism of immune cells will pose no risks. Further, our approach of using dietary factors will be easily tolerated and safe for patient use. We believe that our methodology will increase myelin generation, heal chronic lesions, and treat MS progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310691
Entities
People
- Deepak Kaushik
Organizations
- Memorial University of Newfoundland
- United States Army