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

β-连环蛋白在常染色体显性多囊肾囊肿发生中的作用

基本信息

批准号：
8683329
负责人：
Jordan A Kreidberg
金额：
$ 38.06万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-28 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8683329
关键词：
Accounting Affect Autosomal Dominant Polycystic Kidney Biochemical Biological Process Cell Line Cells Clonal Expansion Complex Cyclic AMP Cyst Cystic kidney Dialysis procedure Disease E-Cadherin End stage renal failure Enzymes Epithelial Epithelial Cells Epithelium Event Failure Family member Gene Targeting Goals Graft Rejection Grant Health Care Costs Hereditary Disease High Prevalence Human Individual Kidney Kidney Diseases Kidney Transplantation Laboratories Magnetic Resonance Imaging Mediating Modeling Modification Molecular Mutation Organ Culture Techniques Pathogenesis Pathway interactions Polycystic Kidney Diseases Post-Translational Protein Processing Process Proprotein Convertase 1 Public Health Quality of life Receptor Protein-Tyrosine Kinases Renal dialysis Renal function Research Role Signal Pathway Signal Transduction Stem cells Structure Testing Therapeutic Therapeutic Intervention Transplantation Treatment Cost Tubular formation Ultrasonography United States Work base beta catenin cost drug discovery frontier human disease impaired productivity inhibitor/antagonist kidney epithelial cell meetings prevent programs public health relevance therapeutic target transcription factor tumor

项目摘要

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.

描述（由申请人提供）：常染色体显性多囊肾病（ADPKD）的特征是患病个体的肾脏内存在大量囊肿。 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，导致肾功能下降并进展为只能通过终身透析或肾移植来治疗的终末期肾病。 ADPKD 是一种最常见的遗传性疾病之一，每 800~1000 个人中就有 1 人受影响。在美国，有 600,000 人患有 PKD，全世界有 1250 万人患有 PKD [1]。因此，ADPKD 是一个重大的公共卫生问题，造成数亿（甚至超过 10 亿）美元的医疗保健费用，特别是透析治疗和预防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。出于所有这些原因，发现直接影响 ADPKD 分子病因并防止进展为终末期肾病以及透析或移植的治疗方法非常重要。在过去的 5 年里，Kreidberg 实验室研究了受体酪氨酸激酶和 Wnt 信号传导在 ADPKD 发病机制中的作用。 Kreidberg 博士的实验室发现 ADPKD 囊肿衬里细胞中 Wnt 信号传导和 β-catenin 表达高度升高。在这笔资助中，他们建议扩展他们的研究，以了解 β-连环蛋白如何整合来自多种途径的信号，从而导致 ADPKD 个体开始形成囊肿。通过了解囊肿发生的过程，我们可以在临床可检测到囊肿发生之前确定抑制囊肿发生或早期进展的治疗靶点。