Investigating the Role of Amino Acid Metabolism in CNS Remyelination
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) that is characterized by demyelination, axonal injury, and progressive neurodegeneration. Several studies suggest that accumulation of chronic active, smoldering lesions in MS may be a key driver of remyelination failure and disease progression, and that therapeutic strategies targeting inflammation resolution may improve remyelination. However, in order to understand the role of inflammation in CNS remyelination, it would be necessary to identify the molecular and cellular changes that occur within the injury environment during remyelination. This proposal addresses the obstacles to repair, and approaches to overcome them and achieve remyelination under the FY20 MSRP Investigator-Initiated Research Award Focus Area Central Nervous System Regenerative Potential in Demyelinating Conditions. In this proposal, we found that an amino acid transporter is highly expressed in the inflamed CNS after demyelination in mice, and inhibiting amino acid transport after demyelination significantly improved remyelination and clinical behavior. Moreover, we found that the regenerative effect from amino acid inhibition was achieved through the reprogramming and restoration of microglia/macrophages in demyelinated lesions back to a homeostatic state. Our goal is to examine how amino acid transport inhibition improves the efficiency of CNS remyelination. We will administer a drug that inhibits amino acid transport into mice that display inefficient remyelination, to see if it can therapeutically promote remyelination. We will also determine the molecular pathways associated with amino acid inhibition on microglia/macrophage function and how restoring these cells to a homeostatic state promotes oligodendrocyte remyelination. Finally, we will determine if mice with a genetic deletion of the acid transporter will exhibit reduced inflammation and improved remyelination. The results of this study will provide insight to the role of amino acid metabolism in CNS remyelination, and why remyelination is impaired under chronic inflammatory environment. Moreover, this study could lead to the future use of a novel drug targeting amino acid transport (which has been shown to be well tolerated in a phase 1 clinical trial for cancer) to prevent chronic active lesion expansion and improve remyelination efficiency in MS, thereby preventing disease progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110964
Entities
People
- Jeffrey K Huang
Organizations
- Georgetown University
- United States Army