Cardiac fibrosis is a major biological determinant in a variety of cardiac diseases including hypertrophy, heart failure, severe arrhythmias and sudden cardiac death. Early interference with fibroblast proliferation to limit fibrosis should be able to prevent fibrogenesis from further perpetuating cardiac diseases. However, Ca2+ signaling mechanisms in cardiac fibroblasts (CFs) have remained elusive. Our long-term goal is to investigate the Ca2+ signaling mechanisms in CFs and their potential roles in fibrotic heart diseases. We have previously cloned a novel bi-functional Ca2+-permeable ion channel TRPM7. Our recent preliminary data showed that: 1) TRPM7 is likely the molecular basis of native TRPM7L, the only Ca2+-permeable ion channel identified in the CFs to date; 2) TRPM7 inward currents can be drastically enhanced by a decrease in extracellular pH; 3) oxidative stress significantly increased TRPM7 inward currents; 4) chronic exposure to TGFb1 up-regulates TRPM7 expression in CFs. Given that acidosis, oxidative stress, and TGFb1 are potent stimuli in initiating fibrogenesis during myocardial injury/infarction, we hypothesize that TRPM7L is essential for Ca2+ signaling in CFs, and plays important roles in myocardial ischemia/infarction initiated fibrogenesis. We propose to: 1) determine if TRPM7 is the molecular basis of TRPM7L, and if TRPM7L underlies Ca2+ signaling mechanisms in CFs under oxidative stress and acidosis stimuli; 2) investigate if chronic fibrogenesis stimuli up-regulate TRPM7L; 3) determine if TRPM7L is essential for CFs' functions in responses to fibrogenesis stimuli. Patch-clamp, Ca2+ imaging, biochemical methods and gene knock-down will be used in this project to reveal the potential roles of TRPM7L-mediated Ca2+ signals in fibrogenesis cascade events. The results of the proposed studies will lead to a future in vivo study which is designed to evaluate potential roles of TRPM7 in cardiac fibrosis using TRPM7 knock out mice, and will ultimately provide clinical insights into therapeutic approaches for fibrosis associated cardiac diseases.
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