Calcium Signaling Mechanisms in Cardiac Fibrogenesis - PROJECT SUMMARY/ABSTRACT Cardiac fibrosis is a hallmark of nearly all forms of heart disease, the leading cause of morbidity and mortality worldwide. However, despite the intensive research, there is no effective therapy for fibrosis, highlighting an urgent need to identify better therapeutic targets. As cardiac fibroblasts are the principal mediators for TGFβ induced fibrosis in heart diseases, targeting a fibroblast-specific molecule which is involved in TGFβ induced fibrosis would be an ideal target. However, fibroblast specific molecules are yet to be discovered. We previously demonstrated that TRPM7 is a major functional Ca2+ permeable channel in cardiac fibroblasts and plays a key role in TGF induced fibrogenesis cascade in cultured fibroblasts. TRPM7 is a unique Ca2+-permeable channel which possess a kinase domain. We have recently discovered that deletion of Trpm7 effectively reduces cardiac fibrosis thereby protecting hearts against pressure-overload induced heart failure. Interestingly, we found that deletion of Trpm7 in fibroblasts is necessary to produce the protective effects, indicating that Trpm7 deletion produces protective effects in a fibroblast-dependent manner. As targeting fibroblasts to inhibit fibrosis has recently been defined as a novel therapeutic strategy for cardiac fibrosis, we propose that TRPM7 may serve as a promising therapeutic target for fibrogenesis. Since TRPM7 has both channel and kinase function, one critical question is whether the channel function or kinase function should be the target for mitigating cardiac fibrosis. We propose two specific aims to investigate whether TRPM7 channel and/or kinase functions contribute to TRPM7 mediated fibrogenesis, and how inhibiting channel and/or kinase functions will protect hearts against fibrosis associated heart diseases. We will apply multidisciplinary approaches including mouse transgenic and knockout models, molecular biology, biochemistry, patch-clamp, Ca2+ imaging, and various in vitro and in vivo disease models, as well as fibroblasts from heart failure patients. The results of this proposal will not only answer the critical questions regarding whether the channel function or kinase activity should be the therapeutic target for fibrogenesis, but also will reveal novel mechanisms of TRPM7-mediated fibrogenesis in fibrosis associated heart diseases. More importantly, this proposal will provide translational insights into therapeutic potential of TRPM7 for pressure overload and ischemic injury induced heart failure.
