Cyclin Dependent Kinases As Drug-Targets To Reduce Renal Cyst Formation and Scarring in Polycystic Kidney Disease

多囊肾病(PKD)是人类最常见的遗传病之一。最常见的类型(常染色体显性遗传性PKD)影响全球约1：400至1：1000的人。肾功能衰竭是PKD最严重、最严重的并发症，约占终末期肾脏需要人工肾治疗(透析)或移植病例的10%。在过去的十年中，在预防糖尿病肾病引起的肾功能衰竭方面取得了重大进展，但这些进展对PKD无效。因此，目前还没有预防PKD引起的肾衰竭的治疗方法，需要新的治疗方法。PKD的特征是在肾脏内发展成多个囊肿，增大并破坏正常的肾组织。包囊的生长是由于肾细胞(上皮细胞)的不受控制的生长(细胞分裂)，这导致了包囊的形成。近年来，被称为多胱氨酸蛋白的蛋白质的基因突变被认为是导致这种疾病的原因。然而，PKD的基因突变是复杂的(仅常染色体显性PKD就有30种类型)，目前的技术在不久的将来不太可能实现基因治疗。一种更简单的方法是开发针对突变后果的“药物”。这个项目将研究一组蛋白质，称为细胞周期蛋白依赖性蛋白激酶(CDKs)在PKD中的作用。CDK是促进细胞分裂的关键酶。我们的初步数据显示，CDK在PKD中表达上调。本项目的目的是确定CDK在PKD中的重要性，并检测新药(CDK抑制剂)在预防PKD的囊性生长和肾脏瘢痕形成中的作用。CDK抑制剂目前正在癌症患者的1期和2期临床试验中进行测试，这将有助于将该项目的结果转化为患有PKD的人类。

Polcystic kidney disease (PKD) is one of the most common genetic diseases in humans. The most common type (autosomal dominant-PKD) affects approximately 1:400 to 1:1000 individuals worldwide. Kidney failure is the most debilitating and serious complication of PKD, and it accounts for approximately 10% of the cases of end-stage kidney requiring artificial kidney treatment (dialysis) or transplantation. Over the last decade, major advances have been made in preventing kidney failure due to diabetic kidney disease, but these are ineffective for PKD. As such, currently, there is no treatment to prevent kidney failure due to PKD, and new therapies are needed. PKD is characterised by the development of multiple cysts in the kidney, which enlarge and destroy normal kidney tissue. The growth of the cysts is due to uncontrolled growth (cell division) of the cells of the kidney (epithelial cells), which causes cyst formation. In recent years, gene mutations in proteins called polcysytins are thought to be responsible for the cause of the disease. However, the genetic mutations in PKD are complex (>30 types for autosomal dominant PKD alone), and it is unlikely that gene therapy will be possible with current technology in the near future. A simpler approach is to develop 'drugs' that target the consequences of the mutation. This project will investigate the role of a group proteins, called cyclin-dependent kinases (CDKs) in PKD. CDKs which are enzymes that are critical in promoting cell division. Our preliminary data shows that CDKs are upregulated in PKD. The aim of this project is to establish the importance of CDKs in PKD, and examine the effect of new drugs (CDK inhibitors) in maintaining in preventing cyst growth and kidney scarring in PKD. CDK inhibitors are currently being tested in phase 1 and 2 clinical trials in patients with cancer, and this will facilitate the translation of the findings of this project to humans with PKD.