KL2 Scholar Scope: Intersection of Small Molecule Inhibitors, Macrophage Polarization, and Gut Immunobiology.

2. Abstract The immune system in the gut contains specialized cells called macrophages that help prevent immune reactions to foods, protect against harmful organisms, and clear out dead cells. In diseases like inflammatory bowel disease (IBD) there is a breakdown in the tissue causing chronic inflammation and certain types of macrophages contribute to the tissue damage. Macrophages exist in two states, one that drives inflammation and another that helps with tissue repair, and in IBD the inflammatory type predominates. New therapies that can shift macrophages into the healing type can help restore gut health and reduce the need for other immunosuppressive drugs. Energy pathways in macrophages determine how they behave and which type they become. While the inflammatory type relies on sugar breakdown through glycolysis, the healing type relies on oxygen-based metabolism via oxidative phosphorylation. A key enzyme called lactate dehydrogenase A (LDHA) drives the end reaction for glycolysis and may be a druggable target. By blocking LDHA we hope to reprogram macrophages to adopt an anti-inflammatory role. This project will use advanced drug-screening methods to identify small molecule inhibitors of LDHA and demonstrate their ability to polarize macrophages to become less inflammatory. The ultimate goal of this project is to develop novel therapies that use metabolic control of macrophages to treat IBD.