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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.

项目总结： -- 常染色体显性遗传性多囊肾综合征(ADPKD)的特点是有大量的囊性病变。在受累个体的肾脏内，在ADPKD中形成的两个囊肿可大大扩大肾脏。肾脏在取代正常的肾脏组织结构的同时，导致肾脏功能和功能的下降。进展到终末期肾脏疾病，只能通过终身肾透析或肾脏移植来治疗。移植。作为一种在800~1000人中影响约1%的常见疾病，ADPKD是最常见的疾病之一。常见的遗传性遗传性疾病。在美国北部，全世界大约有60万人。 1250万，其中包括PKD[1]。因此，ADPKD代表着一个重大的公共卫生和公共卫生问题。在全球医疗保健和医疗成本中，约有数亿美元(甚至可能超过10亿美元)的成本。特别是在透析和治疗方面，并降低了可以防止移植和排斥反应的药物的总成本。此外，这些成本还包括生产率下降和个人生活质量下降的影响。有了ADPKD。考虑到所有这些原因，发现新的治疗方法具有非常重要的意义。直接影响ADPKD的主要分子机制，即它不会阻止ADPKD的进展。肾脏疾病分期，透析或肾移植。 -- 在过去的5年里，克莱德伯格大学的实验室小组一直在调查美国国家石油公司信号系统的主要作用。 ADPKD的主要发病机制。Kreidberg博士的实验室研究发现，Wnt通过信号转导和-？在ADPKD中，连环蛋白的表达在囊肿和衬里细胞中的表达高度升高。在这项拨款中，他们将提出。为了进一步扩大他们的研究范围，他们需要进一步了解一种可能的β-连环蛋白的靶基因纤维连接蛋白是如何影响的。囊性变形成。纤维连接蛋白是一种关键的细胞外基质基因，主要是在一种新的肿瘤中发现的。间充质干细胞基质，但在囊性肾组织中过度表达。我们将继续研究它的主要作用。整合素：纤维连接蛋白及其相互作用在ADPKD中起作用。