The regulation and function of TRPM7 in inflammation

 描述（由申请人提供）：根据 NIH 的数据，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（如阿尔茨海默病、动脉粥样硬化和 2 型糖尿病）的进展和病理有重要影响。通过使用生物药物阻断促炎途径（例如 TNF 受体信号传导）来治疗严重炎症性疾病。但临床结果往往是不确定的，并且受到严重不良反应的困扰。因此，通过更实惠的小分子来表征这些“可成药”的炎症途径的新型调节剂具有临床和经济意义。 TRP 通道是一类令人兴奋的药物靶点，其在炎症中的功能仍不清楚。 TRPM7 是一种包含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。通过生成 Trpm7 整体和组织特异性缺失的小鼠品系，我们发现了 TRPM7 在免疫系统中的关键作用，现在，我们发现了 TRPM7 在巨噬细胞激活（炎症中的重要检查点）中的显着作用。我们的中心假设是：Caspase 介导的 TRPM7 蛋白水解调节对于巨噬细胞中的炎症信号传导至关重要。我们的具体目标是：（1）明确巨噬细胞中炎症性半胱天冬酶对TRPM7的调节作用； (2)定义TRPM7在巨噬细胞Fas和TLR4信号传导过程中的功能。确定半胱天冬酶介导的 TRPM7 裂解如何在巨噬细胞激活过程中控制 Fas 和 TLR4 信号传导将推动 TRPM7 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.