The Proteolytic Cleavage of Polycystin-1: How and Why

描述（由申请方提供）：常染色体显性遗传性多囊肾病（ADPKD）是人类最常见的孟德尔疾病之一，在全球范围内的发病率为1/1000。这种疾病的标志是在双肾中从肾小管发展出多个囊肿，导致50%的患者出现终末期肾衰竭。ADPKD是一种具有多种肾外表现的全身性疾病。自从PKD 1基因在1995年被发现以来，人们在了解该疾病的生物学基础方面做出了重大努力。但其基因产物多囊蛋白-1的正常功能仍然知之甚少。单个PKD 1基因的突变如何导致大量缺陷的问题也没有得到解决。 我们研究的长期目标是了解多囊蛋白-1在发育过程中的正常生物学功能及其在维持成人器官中的作用，以及PKD 1突变导致疾病的机制。已知蛋白质的翻译后修饰对其活性起关键作用，并且此类过程与多囊蛋白-1的功能有关。我们已经发现，多囊蛋白-1在体内进行蛋白水解切割。我们的初步结果表明，这种类型的翻译后过程可能是重要的多囊蛋白-1的功能。 在资助申请中，我们建议使用化学，生物化学，遗传学和细胞生物学方法的组合来研究多囊蛋白-1的蛋白水解裂解的作用。我们计划在细胞培养系统和小鼠中研究这一过程的功能意义。此外，我们建议的特点，裂解反应的调节机制和分析的过程中的细胞机器。这一科学质疑可能会为Potycystin-1的功能和新的调控机制提供重要的见解。我们的研究也可能提供PKD 1突变导致疾病的机制的线索。本研究的信息将为ADPKD的研究开辟新的途径，并为开发ADPKD的病因和有效治疗方法奠定基础。

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common Mendelian disorders in humans affecting 1/1000 worldwide. The hallmark of the disease is the development of multiple cysts from renal tubules in both kidneys, resulting in end-stage renal failure in 50% of the patients. ADPKD is a systemic disease with many ex-renal manifestations. Since the PKD1 gene was identified in 1995, significant efforts have been made in understanding of the biology underlying the disease. But the normal function its gene product, polycystin-1, is still poorly understood. The question of how a mutation in the single PKD1 gene leads to a vast array of defects is also unresolved. The long-term goal of our research is to understand the normal biological function of polycystin-1 during the development and its role in the maintenance of adult organs, and the mechanisms by which PKD1 mutations cause the disease. Post-translational modifications of the protein are known to play a critical role for its activity and such processes have been implicated for the function of polycystin-1. We have found that polycystin-1 undergoes proteolyctic cleavage in vivo. Our preliminary results have indicated that this type of the post-translational processes is likely important for the functionality of polycystin-1. In the grant application, we propose to investigate the role of the proteolytic cleavage of polycystin-1 using a combination of chemical, biochemical, genetic and cell biological approaches. We plan to examine the functional significance of this process in the cell culture system and in the mouse. Furthermore, we propose to characterize the mechanism of regulation of the cleavage reaction and analyze the cellular machinery of the process. This scientific query will likely provide important insights into the functions and novel mechanism of the regulation of potycystin-1. Our investigation will also likely provide clues of the mechanisms by which PKD1 mutations cause the disease. The information from our studies will likely open new avenues in the research of ADPKD and establish the foundation for developing causative and effective therapies of the disease.