Ion-channel targeted therapy for progressive kidney diseases

进行性肾脏疾病的离子通道靶向治疗

基本信息

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
项目类别：
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

项目摘要

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脏疾病在全球范围内增加，超过500 百万人受到影响，但没有有效的疗法可以阻止他们的发展肾衰竭。高血压和糖尿病仍然是进步的最大驱动力全球肾脏疾病。一个大挑战是特定的分子和肾脏参与肾脏疾病进展的细胞仍然了解不足。我们最近由这笔赠款资助的工作揭示了两个这样的分子Rac1和Trpc5，为负责称为足细胞的贵肾细胞的损伤和死亡。损失足细胞导致蛋白尿，蛋白尿，肾脏过滤屏障的标志和最终肾衰竭。由这笔赠款资助，我们还发现了一个TRPC5阻滞剂，称为AC1903，这可以防止Rac1-TRPC5损伤足细胞。在两个肾脏的老鼠模型中疾病称为FSG（局灶性和分段肾小球硬化），我们表明AC1903 防止肾脏过滤器损伤和受保护的足细胞，使其成为极好的为患者开发未来治疗的候选人。但是，目前尚不清楚AC1903或其他TRPC通道阻滞剂是否可以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，此修订后的竞争续约应用的目的是建立我们最近的发现并在大鼠和鼠标模型中进行仔细的研究进行性肾脏疾病以进一步了解TRPC离子通道的作用以及他们在治疗与高血压相关的肾脏疾病方面的阻滞剂糖尿病。这项工作将为肾脏病患者的新疗法铺平道路，非常需要。