The Proteolytic Cleavage of Polycystin-1: How and Why

描述(申请人提供)：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，在全球范围内影响千分之一。本病的特点是双侧肾小管形成多个囊性病变，导致50%的患者出现终末期肾功能衰竭。ADPKD是一种具有多种肾外表现的全身性疾病。自从1995年PKD1基因被发现以来，人们在了解该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PKD1基因的突变如何导致大量缺陷的问题也没有解决。 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成人器官维护中的作用，以及PKD1突变导致疾病的机制。已知该蛋白的翻译后修饰对其活性起关键作用，并且这种过程与多囊蛋白-1的功能有关。我们发现多囊蛋白-1在体内发生了蛋白水解性切割。我们的初步结果表明，这种类型的翻译后过程可能对多囊蛋白-1的功能很重要。 在赠款申请中，我们建议结合化学、生化、遗传和细胞生物学的方法来研究多囊蛋白-1的蛋白分解作用。我们计划研究这一过程在细胞培养系统和小鼠体内的功能意义。此外，我们建议表征切割反应的调节机制，并分析这一过程的细胞机制。这一科学质疑可能会为了解藻毒素-1的功能和新的调控机制提供重要的见解。我们的研究还可能提供PKD1突变导致疾病的机制的线索。我们研究的信息可能会为ADPKD的研究开辟新的途径，并为开发致病和有效的治疗方法奠定基础。

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.