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The Role of Fibronectin in ADPKD

纤连蛋白在 ADPKD 中的作用

基本信息

批准号：
10217127
负责人：
Jordan A Kreidberg
金额：
$ 28.52万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217127
关键词：
Affect Alleles Autosomal Dominant Polycystic Kidney Biochemical Cell Adhesion Cells Cyst Cyst Fluid Cystic kidney Dialysis procedure Disease Drug Costs ECM receptor End stage renal failure Epithelial Extracellular Matrix Extracellular Matrix Proteins Family Fibronectin Receptors Fibronectins Gene Silencing Genes Genetic Diseases Graft Rejection Grant Health Care Costs Hereditary Disease High Prevalence Impairment Individual Industrialization Integrin Binding Integrin alpha Chains Integrins Intervention Kidney Kidney Transplantation Laboratories Lead Ligands Mesenchymal Molecular Mus Mutation PKD1 gene PKD2 gene PTK2 gene Pathogenesis Pharmacologic Substance Pharmacology Prevention Productivity Property Public Health Quality of life Receptor Protein-Tyrosine Kinases Renal dialysis Renal function Role Signal Transduction Signal Transduction Pathway Structure Therapeutic Transforming Growth Factor beta Transplantation Treatment Cost United States WNT Signaling Pathway Work apical membrane base beta catenin conditional knockout conditional mutant cost fibrillogenesis gene product inhibitor/antagonist kidney epithelial cell mouse model mutant overexpression prevent single cell sequencing transcriptome sequencing

项目摘要

Project Summary 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 drugs 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 importance 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 Wnt signaling in the pathogenesis of ADPKD. Dr. Kreidberg’s laboratory has found that Wnt signaling and β- catenin expression is highly elevated in cyst lining cells in ADPKD. In this grant they propose to extend their studies to understand how a putative β-catenin target gene, fibronectin, affects cyst formation. Fibronectin is a key extracellular matrix gene primarily found in a mesenchymal matrix, but over-expressed in cystic kidneys. We will study the role of integrin:fibronectin interactions in ADPKD.

项目摘要常染色体显性遗传性多囊肾病（ADPKD）的特征是大量囊肿在患病个体的肾脏内。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，进展为终末期肾病，只能通过终身透析或肾脏治疗作为一种影响800~1000个人中1人的疾病，ADPKD是最常见的疾病之一。常见的遗传疾病。在美国，有600，000人，全世界 12.5 100万，PKD [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（也许超过十亿美元），特别是透析治疗和防止移植排斥反应的药物费用，以及生产力下降和个人生活质量受损所涉及的成本由于所有这些原因，发现治疗方法非常重要，直接影响ADPKD的分子病因，这将阻止进展到终末期肾病。分期肾病和透析或移植。在过去的5年里，Kreidberg实验室研究了Wnt信号在 Kreidberg博士的实验室发现，Wnt信号和β-淀粉样蛋白在ADPKD的发病机制中起着重要作用。连环蛋白在ADPKD囊肿衬里细胞中的表达高度升高。扩展他们的研究，以了解一个假定的β-catenin靶基因，纤连蛋白，纤维连接蛋白是一种关键的细胞外基质基因，主要发现于间充质基质，但过度表达在囊性肾。我们将研究的作用，整合素：ADPKD中纤连蛋白的相互作用。