TRPM7-mediated macrophage signaling in atherosclerosis

ABSTRACT Atherosclerosis is a cardiovascular disease that underlies 50% of all deaths in Western societies. This disease is characterized by chronic inflammation and lipid-laden plaque buildup on the interior of major arteries, and the risk factors for atherosclerosis can be due to genetic and/or environmental factors. The major cell type involved in atherogenesis is macrophages, which are necessary for the uptake and clearance of inflammatory lipoprotein molecules. Dysfunctional lipoprotein metabolism by macrophages can cause macrophages to become trapped within the intimal wall of arterial vessels, leading to a positive inflammatory cascade of macrophage trapping, macrophage death, and increased immune recruitment and elevated inflammation in the atherosclerotic tissues. “Transient receptor potential protein, melastatin family member 7” (TRPM7) is a part of the larger “TRP” family of channels. This family of channels is highly implicated in cellular sensing of ligands and extracellular stressors. TRPM7 is a unique channel due to its functional kinase domain. Thus, TRPM7 is often termed as a “channel- enzyme”, or “chanzyme”. Using a translationally relevant atherosclerosis model, we have recently found that TRPM7, specifically the TRPM7 channel domain, is involved in atherogenesis, and that Trpm7 deletion is sufficient to reduce atherosclerotic phenotypes. Furthermore, my pilot studies suggest a pro-inflammatory role of TRPM7 channel function in macrophages in vitro. Accordingly, in Aim 1, we will generate macrophage-specific TRPM7 deletion mice and subject them to a translationally significant atherosclerosis model involving a high-fat, Western diet. We will determine how the in vivo deletion of macrophage TRPM7 affects atherosclerotic phenotypes, including plaque size, plaque stability, immune cell infiltration and recruitment, and inflammatory status. This model will provide valuable insight into the in vivo role of macrophage TRPM7 in the development of atherosclerosis. Aim 2 will determine the role of TRPM7 signaling in inflammatory pathways in macrophages and aid us in understanding how ion channels can modulate cellular responses in response to extracellular stimuli. Additionally, the use of primary human macrophages will help us to identify a valuable translational impact of TRPM7-mediated inflammatory signaling in a clinically relevant manner. The long-term goal of this exciting project is to uncover a specific, cell-specific target for the treatment of atherosclerotic individuals. This highly translational project will provide me with exciting opportunities to conduct multidisciplinary investigations. The training goals developed by my sponsor and me will lead to novel discoveries and will contribute greatly to my career goal of becoming an independent research scientist. Collectively, this current proposal will foster and support me to take full advantage of the intellectual community and resources that are available to me via the UConn Health network.