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性疾病之一。最常见的类型（常染色体显性-PKD）影响全球约1：400至1：1000的个体。肾衰竭是PKD最虚弱和最严重的并发症，它占需要人工肾治疗（透析）或移植的终末期肾脏病例的约10%。在过去的十年中，在预防糖尿病肾病引起的肾衰竭方面取得了重大进展，但这些对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的特征是肾脏中多个囊肿的发展，这些囊肿扩大并破坏正常的肾脏组织。囊肿的生长是由于肾脏细胞（上皮细胞）的不受控制的生长（细胞分裂），导致囊肿形成。近年来，被称为polcysytins的蛋白质中的基因突变被认为是导致这种疾病的原因。然而，PKD中的基因突变是复杂的（仅常染色体显性PKD就有30种类型），并且在不久的将来，基因治疗不太可能在现有技术下实现。一种更简单的方法是开发针对突变后果的“药物”。本项目将研究一组蛋白质，称为细胞周期蛋白依赖性激酶（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中上调。本项目的目的是确定CDK在PKD中的重要性，并检查新药（CDK抑制剂）在维持PKD中防止囊肿生长和肾瘢痕形成方面的作用。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发现转化为PKD患者。

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.