The regulation and function of TRPM7 in inflammation

 描述（由申请人提供）：根据NIH，2050万美国人患有自身免疫性疾病。此外，炎症对一些与年龄相关的疾病的进展和病理学有重要作用，如阿尔茨海默病、动脉粥样硬化和2型糖尿病。严重的炎性疾病通过使用生物药物阻断促炎途径（如TNF受体信号传导）来治疗。但临床结果往往是不确定的，并受到严重不良反应的困扰。因此，通过更实惠的小分子表征这些炎症途径的“可药物化”的新型调节剂具有临床和经济意义。TRP通道是一类激动人心的药物靶点，其在炎症中的功能尚不清楚。TRPM 7是一种含有阳离子传导孔和激酶结构域的TRP通道，在免疫细胞中高度表达。通过产生具有Trpm 7的全局和组织特异性缺失的小鼠品系，我们发现了TRPM 7在免疫系统中的关键作用，现在，我们已经发现了TRPM 7在巨噬细胞活化中的惊人作用，巨噬细胞活化是炎症中的一个重要检查点。我们的中心假设是：胱天蛋白酶介导的TRPM 7蛋白水解调节是必不可少的炎症信号在巨噬细胞。我们的具体目标是：（1）确定巨噬细胞中炎性半胱天冬酶对TRPM 7的调节;（2）确定TRPM 7在巨噬细胞中Fas和TLR 4信号传导过程中的功能。在巨噬细胞活化过程中，确定半胱天冬酶介导的TRPM 7切割如何控制Fas和TLR 4信号传导，将促进TRPM 7作为炎症性疾病的分子靶点。多学科方法、新型小鼠品系和创新分子试剂的整合使我们能够填补这一对人类炎症性疾病具有广泛意义的空白。

 DESCRIPTION (provided by applicant): According to the NIH, 20.5 million Americans suffer from autoimmune diseases. Additionally, inflammation contributes potently to the progression and pathology of some age-related diseases, such as Alzheimer's disease, atherosclerosis and type 2 diabetes. Severe inflammatory diseases are treated by blocking the pro-inflammatory pathways, such as TNF receptor signaling, using biological drugs. But the clinical outcome is often uncertain and plagued by significant adverse effects. Characterization of novel regulators of these inflammatory pathways that are "druggable", by more affordable small molecules is therefore of clinical and economic significance. The function of TRP channels, an exciting class of drug targets, in inflammation remains undefined. TRPM7, a TRP channel that contains a cation-conducting pore and a kinase domain, is highly expressed in the immune cells. By generating mouse lines with global and tissue-specific deletion of Trpm7, we discovered a crucial role for TRPM7 in the immune system, and now, we have uncovered a striking role for TRPM7 in macrophage activation, an essential checkpoint in inflammation. Our central hypothesis is that: Caspase-mediated proteolytic regulation of TRPM7 is essential for inflammatory signaling in macrophages. Our specific aims are: (1) Define the regulation of TRPM7 by inflammatory caspases in macrophages; (2) Define the function of TRPM7 during Fas and TLR4 signaling in macrophages. Defining how caspase-mediated cleavage of TRPM7 controls Fas and TLR4 signaling during macrophage activation will advance TRPM7 as a molecular target in inflammatory diseases. Integration of multidisciplinary approaches, novel mouse lines and innovative molecular reagents uniquely position us to fill this gap of broad significance to inflammatory diseases in humans.