The regulation and function of TRPM7 in inflammation

 描述(申请人提供)：根据美国国立卫生研究院的数据，有2050万美国人患有自身免疫性疾病。此外，炎症在一些与年龄相关的疾病的进展和病理中起着重要作用，如阿尔茨海默病、动脉粥样硬化和2型糖尿病。严重的炎症性疾病是通过使用生物药物阻断促炎通路，如肿瘤坏死因子受体信号通路来治疗的。但临床结果往往是不确定的，并受到重大不良反应的困扰。因此，通过更经济实惠的小分子来表征这些“可用药”的炎性通路的新型调节因子具有临床和经济意义。色氨酸通道是一类令人兴奋的药物靶点，其在炎症中的作用尚不清楚。TRPM7是一种Trp通道，它含有一个阳离子传导孔和一个激活域，在免疫细胞中高度表达。通过建立Trpm7的全局和组织特异性缺失的小鼠株系，我们发现TRPM7在免疫系统中发挥着至关重要的作用，现在，我们已经发现TRPM7在巨噬细胞激活中的显著作用，巨噬细胞激活是炎症中的一个重要检查点。我们的中心假设是：caspase介导的TRPM7的蛋白降解调节对于巨噬细胞的炎症信号是必不可少的。我们的具体目标是：(1)明确巨噬细胞中炎性caspase对TRPM7的调节；(2)明确TRPM7在巨噬细胞Fas和TLR4信号转导中的作用。明确caspase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，将推动TRPM7成为炎症性疾病的分子靶点。多学科方法、新的小鼠品系和创新的分子试剂的集成使我们能够独特地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.