Role of TRPC5 channel inhibition in the treatment of glomerular disease

描述（由申请方提供）：足细胞细胞骨架损伤的特征在于Ca2+信号传导失调和足细胞运动性增加，这与足细胞足突（FP）塌陷和白蛋白尿的出现相关。我们的实验室表明，增加足细胞运动是由TRPC 5介导的，TRPC 5是我们实验室几年前引入的一种离子通道，是足细胞中重要的Ca2+内流途径。基于我们最近的工作，TRPC 5通道在急性疾病模型中蛋白尿的出现中起重要作用。然而，关于足细胞TRPC 5信号在获得性肾小球疾病（如FSGS）慢性化中的作用知之甚少，这是本提案的重点。了解涉及TRPC 5活性的机制步骤以及如何阻断它对于许多患有新发特发性肾病综合征（如FSGS）的儿童和成人、移植后FSGS复发的毁灭性病例以及数百万患有糖尿病和高血压背景下的白蛋白尿和FSGS的患者非常重要。不幸的是，我们目前缺乏对这些患者的有效治疗，因此在这一治疗领域存在巨大的未满足需求。在这里，我们提出了一系列详细的体内研究，以测试的假设，使用小分子抑制剂阻断TRPC 5通道可以防止进展到FSGS和肾衰竭。

DESCRIPTION (provided by applicant): Podocyte cytoskeletal injury is characterized by dysregulation of Ca2+ signaling and increased podocyte motility, which correlate with podocyte foot process (FP) collapse and the emergence of albuminuria. Our laboratory showed that increased podocyte motility is mediated by TRPC5, an ion channel our laboratory introduced a few years ago as an important Ca2+ influx pathway in podocytes. Based on our recent work, TRPC5 channels play an important role in the emergence of albuminuria in acute models of disease. However, little is known about the role of podocyte TRPC5 signaling in the chronicity of acquired glomerular disease such as FSGS, which is the focus of this proposal. Understanding the mechanistic steps involving TRPC5 activity and how to block it is important for the many children and adults with de novo idiopathic Nephrotic Syndrome (such as FSGS), for the devastating cases of recurrence of FSGS post-transplantation and for the millions of patients with albuminuria and FSGS in the setting of diabetes and hypertension. Unfortunately, we presently lack effective treatment for these patients, so there is tremendous unmet need in this therapeutic area. Here we propose a series of detailed in vivo studies to test the hypothesis that blocking TRPC5 channels using a small molecule inhibitor can prevent progression to FSGS and kidney failure.