Role of TRPC5 channel inhibition in the treatment of glomerular disease

TRPC5通道抑制在肾小球疾病治疗中的作用

• 批准号: 9121550
• 负责人: Anna Greka
• 金额: $ 36.63万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121550
• 关键词: Acute; Adult; Albuminuria; Area; Biopsy; Calcium; Cell Death; Child; Data; Diabetes Mellitus; Disease; Disease Progression; Disease model; Dose; Focal Segmental Glomerulosclerosis; Foot Process; Goals; Health; Human; Hypertension; Image; In Situ; In Vitro; Injury; Ion Channel; Kidney Diseases; Kidney Failure; Knockout Mice; Laboratories; Lipopolysaccharides; Mediating; Messenger RNA; Modeling; Molecular; Mus; Mutation; Nephrotic Syndrome; Pathway interactions; Patients; Personal Communication; Play; Protamine Sulfate; Publishing; Recurrence; Renal glomerular disease; Role; Series; Signal Transduction; Testing; Therapeutic; Time; Transplantation; Work; arm; base; cell motility; effective therapy; human disease; in vivo; inhibitor/antagonist; novel; novel therapeutics; podocyte; prevent; role model; small molecule inhibitor; synaptopodin; therapeutic target

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.

描述（由申请人提供）：足细胞细胞骨架损伤的特征是CA2+信号传导失调和足细胞运动性增加，这与Podocyte脚步过程（FP）崩溃以及蛋白尿的出现相关。我们的实验室表明，增强的足细胞运动性是由TRPC5介导的，TRPC5是几年前我们的实验室引入的一个离子通道，它是足细胞中重要的Ca2+涌入途径。根据我们最近的工作，TRPC5通道在疾病急性模型中蛋白尿的出现中起着重要作用。然而，对足细胞TRPC5信号传导在获得的肾小球疾病（例如FSG）的慢性性中的作用知之甚少，FSG是该提案的重点。了解涉及TRPC5活性的机械步骤以及如何阻止它对于许多新的特发性肾病综合征（例如FSGS），对于FSG转移后的FSG复发的毁灭性案件以及数以百万计的白蛋白尿和FSGS和Hypersense和Hyperterse的患者而言。不幸的是，我们目前缺乏对这些患者的有效治疗方法，因此在这个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，以检验以下假设：使用小分子抑制剂阻止TRPC5通道可以防止向FSG和肾衰竭发展。