Role of TRPC5 channel inhibition in the treatment of glomerular disease

描述(申请人提供)：足细胞细胞骨架损伤的特征是钙信号调节失调和足细胞运动性增加，这与足细胞足突(FP)塌陷和蛋白尿的出现有关。我们的实验室发现，足细胞运动能力的增加是由TRPC5介导的，TRPC5是我们实验室几年前引入的一种离子通道，是足细胞内钙内流的重要途径。根据我们最近的工作，TRPC5通道在急性疾病模型中蛋白尿的出现中起着重要作用。然而，足细胞TRPC5信号在获得性肾小球疾病(如FSGS)慢性化中的作用知之甚少，这也是本研究的重点。了解涉及TRPC5活性的机制步骤以及如何阻断它对于许多患有新生特发性肾病综合征(如FSGS)的儿童和成人、FSGS移植后毁灭性的复发病例以及数百万糖尿病和高血压合并蛋白尿和FSGS患者来说非常重要。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得到满足的需求。在这里，我们提出了一系列详细的体内研究，以验证使用小分子抑制剂阻断TRPC5通道可以防止进展为FSGS和肾衰竭的假设。

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.