The role of beta-catenin in cyst initiation in Autosomal Dominant Polycystic Kidn

描述（由申请人提供）：常染色体显性多囊肾病（ADPKD）的特点是患者肾脏内有许多囊肿。在ADPKD中形成的囊肿可以极大地扩大肾脏，同时取代正常的肾脏结构，导致肾功能下降，发展为终末期肾脏疾病，只能通过终身透析或肾脏移植来治疗。ADPKD是最常见的遗传性疾病之一，发病率为1 / 800~1000。在美国，有60万人，全世界有1250万人患有PKD。因此，ADPKD是一个重大的公共卫生问题，其医疗保健费用高达数亿美元（甚至可能超过10亿美元），特别是透析治疗和防止移植排斥的药物费用，以及ADPKD患者生产力下降和生活质量受损所涉及的费用。由于这些原因，发现直接影响ADPKD分子原因的治疗方法非常重要，这将防止进展为终末期肾脏疾病和透析或移植。在过去的5年里，Kreidberg实验室研究了受体酪氨酸激酶和Wnt信号在ADPKD发病机制中的作用。Kreidberg博士的实验室发现，在ADPKD的囊肿衬里细胞中，Wnt信号和β -连环蛋白的表达高度升高。在这项资助中，他们提议扩展他们的研究，以了解b-连环蛋白如何整合来自许多途径的信号，从而导致ADPKD患者开始形成囊肿。通过了解囊肿形成的过程，我们可以在临床检测到囊肿之前确定抑制囊肿形成或早期发展的治疗靶点。

DESCRIPTION (provided by applicant): Autosomal Dominant Polycystic kidney disease (ADPKD) is characterized by numerous cysts within the kidneys of afflicted individuals. The cysts formed in ADPKD can greatly enlarge the kidneys while replacing the normal kidney structures, resulting in reduced kidney function and progression to end-stage renal disease that can only be treated by lifelong dialysis or kidney transplants. As a disease that affects 1 in 800~1000 individuals, ADPKD is among the most common genetic disorders. In the United States, there are 600,000 individuals, and worldwide 12.5 million, with PKD [1]. Thus, ADPKD represents a major public health issue, and accounts for hundreds of millions (and perhaps over a billion) of dollars in health care costs, particularly for dialysis treatments and the cost of drgs that prevent transplant rejections, as well as the cost involved of decreased productivity and impaired quality of life of individuals with ADPKD. For all these reasons, it is of great importanc to discover treatments that directly affect the molecular causes of ADPKD, and that will prevent the progression to end- stage renal disease and dialysis or transplantation. Over the past 5 years the Kreidberg laboratory has investigated the role of receptor tyrosine kinase and Wnt signaling in the pathogenesis of ADPKD. Dr. Kreidberg's laboratory has found that Wnt signaling and beta-catenin expression is highly elevated in cyst lining cells in ADPKD. In this grant they propose to extend their studies to understand how b-catenin integrates signals from many pathways to cause the initiation of cyst formation in individuals with ADPKD. By understanding the processes involved in the initiation of cysts, we may identify therapeutic targets that inhibit the initiation or early progression of cysts, before they are clinically detectable.