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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：
9064636
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/9064636
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 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 differential expression drug discovery frontier human disease impaired productivity inhibitor/antagonist kidney epithelial cell meetings prevent programs targeted treatment 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)：常染色体显性遗传性多囊肾病(ADPKD)的特征是患者的肾脏内有大量的囊肿。ADPKD中形成的囊变可使肾脏大大增大，同时取代正常的肾脏结构，导致肾功能下降，进展为终末期肾脏疾病，只能通过终生透析或肾移植来治疗。ADPKD是一种每800~1000人中就有1人患病的疾病，是最常见的遗传病之一。在美国，有60万人患有PKD，全世界有1250万人[1]。因此，ADPKD是一个重大的公共卫生问题，占医疗保健费用的数亿美元(或许超过10亿美元)，特别是用于透析治疗的费用和防止移植排斥反应的DRGs费用，以及ADPKD患者生产力下降和生活质量受损的费用。因此，寻找直接影响ADPKD分子病因的治疗方法，防止进展为终末期肾病和透析或移植是非常重要的。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的囊壁细胞中，Wnt信号和β-catenin的表达高度升高。在这项授权中，他们建议扩展他们的研究，以了解b-catenin如何整合来自许多途径的信号，从而导致ADPKD患者的囊性形成。通过了解囊性病变的发生过程，我们可以在临床可察觉之前，确定抑制囊肿性病变发生或早期进展的治疗靶点。