Ion-channel targeted therapy for progressive kidney diseases

进行性肾脏疾病的离子通道靶向治疗

• 批准号: 10216240
• 负责人: Anna Greka
• 金额: $ 38.48万
• 依托单位: BROAD INSTITUTE, INC.
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216240
• 关键词: Affect; Animal Model; Area; Calcium; Cell membrane; Cessation of life; Clinical; Creatinine; Dahl Hypertensive Rats; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Disease; Disease Progression; Focal Segmental Glomerulosclerosis; Foot Process; Funding; Future; Goals; Grant; Health; High Fat Diet; Histologic; Human; Hypertension; In Vitro; Injury; Ion Channel; Kidney; Kidney Diseases; Kidney Failure; Laboratories; Mediating; Medical; Modeling; Mus; Mutation; Nephrosis; Obesity; Pathway interactions; Patients; Proteinuria; Publishing; Puromycin Aminonucleoside; Rattus; Rodent; Rodent Model; Role; Science; Signal Transduction; Testing; Therapeutic; Time; Transgenic Organisms; Treatment Efficacy; Work; base; cell motility; channel blockers; diabetic; effective therapy; efficacy testing; in vivo; inhibitor/antagonist; insight; kidney cell; loss of function mutation; mouse model; novel; novel therapeutics; podocyte; preservation; prevent; small molecule inhibitor; targeted treatment

PROJECT SUMMARY Progressive proteinuric kidney diseases are on the rise worldwide with more than 500 million people affected, and yet no effective therapies exist to halt their progression to kidney failure. High blood pressure and diabetes remain the biggest drivers of progressive kidney diseases worldwide. One big challenge is that the specific molecules and kidney cells involved in progression of kidney diseases remain poorly understood. Our recent work funded by this grant revealed two such molecules, Rac1 and TRPC5, as responsible for the injury and death of precious kidney cells called podocytes. Loss of podocytes resulted in proteinuria, the hallmark of a broken kidney filter barrier and ultimate kidney failure. Funded by this grant, we also discovered a TRPC5 blocker, called AC1903, which can prevent Rac1-TRPC5 from injuring podocytes. In two rat models of a kidney disease called FSGS (Focal and Segmental Glomerulosclerosis), we showed that AC1903 prevented kidney filter damage and protected podocytes, making this an excellent candidate for the development of a future therapy for patients. However, at this time, it is not clear if AC1903 or other TRPC channel blockers can be helpful in protecting the kidneys of patients with hypertension or diabetes-related kidney diseases. Therefore, the goal of this revised competitive renewal application is to build on our recent discoveries and perform careful and detailed studies in rat and mouse models of progressive kidney diseases to gain further insight into the role of TRPC ion channels and their blockers in the treatment of kidney diseases associated with hypertension and diabetes. This work will pave the way for new therapies for kidney disease patients, which are greatly needed.

项目摘要 进行性蛋白尿肾病在全球范围内呈上升趋势， 数百万人受到影响，但没有有效的治疗方法来阻止他们的进展， 肾衰竭高血压和糖尿病仍然是进步的最大驱动力 世界各地的肾脏疾病一个巨大的挑战是，特定的分子和肾脏 参与肾脏疾病进展的细胞仍然知之甚少。 我们最近的工作由该基金资助，揭示了两个这样的分子，Rac 1和TRPC 5， 导致珍贵的肾细胞足细胞的损伤和死亡。损失 足细胞导致蛋白尿，这是肾脏滤过屏障破坏的标志， 肾衰竭在这笔资金的资助下，我们还发现了一种TRPC 5阻断剂，称为AC 1903， 其可以防止Rac 1-TRPC 5损伤足细胞。在两个大鼠肾脏模型中， 一种叫做FSGS（局灶性和节段性肾小球硬化）的疾病，我们发现AC 1903 防止肾过滤器损伤和保护足细胞，使其成为一个很好的 为患者开发未来疗法的候选人。 然而，目前尚不清楚AC 1903或其他TRPC通道阻断剂是否可以用于治疗。 有助于保护高血压或糖尿病相关肾脏患者的肾脏 疾病因此，修订后的竞争性续约申请的目标是建立在 我们最近的发现，并在大鼠和小鼠模型中进行了仔细和详细的研究， 进一步了解TRPC离子通道的作用 及其阻断剂在治疗与高血压相关的肾病中的应用， 糖尿病这项工作将为肾病患者的新疗法铺平道路， 非常需要。