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: 8927620
• 负责人: Anna Greka
• 金额: $ 36.61万
• 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/8927620
• 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; 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。我们的实验室表明，足细胞运动的增加是由TRPC5介导的，TRPC5是我们实验室几年前引入的一种离子通道，是足细胞中重要的Ca2+内流途径。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重要作用。然而，足细胞TRPC5信号在获得性肾小球疾病（如FSGS）的慢性性中的作用知之甚少，这是本提案的重点。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发特发性肾病综合征（如FSGS）的儿童和成人，对于移植后FSGS复发的破坏性病例以及数百万患有糖尿病和高血压的蛋白尿和FSGS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有巨大的未满足需求。在这里，我们提出了一系列详细的体内研究，以验证使用小分子抑制剂阻断TRPC5通道可以防止FSGS和肾衰竭进展的假设。