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Understanding the role of kinase inhibitors on the formation of lipid-laden foamy macrophages at the spinal cord injury site
Location: 45
Mentor: Dr. Jae Lee
Spinal cord injury (SCI) is hallmarked by high levels of inflammation, including an increase in phagocytic cells, microglia, and macrophages. An abundance of lipid debris accumulates at thetissue and myelin, dead or damaged cells, and other sources. This leads to the formation of foamy macrophages which are pro-inflammatory and persist in the injured cord for extended periods, significantly contributing to secondary injuries. Preventing foamy macrophage formation is an unexplored neuroprotective strategy for SCI. We hypothesized that druggable kinases can be identified for preventing foamy macrophage formation. We developed an in vitro foamy macrophage assay and deployed it with our target identification platform (idTRAX). The platform identified kinases whose inhibition prevents foamy macrophage formation. These identified kinase targets were validated in vitro using selective chemical probes and Lentivirus knockdown. Compounds that demonstrate the highest efficacy in vitro were then administered to SCI mice. It was found that selective PI3K, BTK, and SRC inhibitors reduced foamy macrophage formation in bone marrow derived macrophages (BMDM), splenic monocyte derived macrophages (spMDM), and human blood monocyte derived macrophages (huMDM). Further, PI3K and BTK knockdown using Lentivirus shows promising results in reducing lipid spots in RAW 264.7 cells. Future steps include adding experimental replicates with Lentivirus, quantification of free BTK and SRC inhibitors in acute timepoint tissue and adding chronic timepoint studies.
