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Mechanisms of ADPKD cystogenesis

ADPKD 囊肿发生机制

基本信息

批准号：
9103618
负责人：
Gabriele Luca GUSELLA
金额：
$ 38.14万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-05 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9103618
关键词：
Ablation Address Affect Architecture Autosomal Dominant Polycystic Kidney Bilateral Biological Preservation Cell Proliferation Cell physiology Cells Cilia Clinical Code Complex Cues Cyst Cystic Kidney Diseases Cystic kidney Cytogenetics Data Defect Development Dilatation - action Disease Disease Progression Duct (organ) structure ECM receptor End stage renal failure Epidermal Growth Factor Receptor Epithelium Event Extracellular Matrix Focal Adhesions Gene Mutation Genes Genetic Genetic Models Germ-Line Mutation Growth Factor Receptors In Vitro Incidence Individual Integrin Inhibition Integrins Investigation Kidney Life Liquid substance Maintenance Mechanical Stimulation Mediator of activation protein Membrane Mendelian disorder Modeling Molecular Multiprotein Complexes Mus Nature Organ PKD1 gene PKD2 gene PKD2 protein Pathogenesis Pathway interactions Phenotype Prevention Process Protein Analysis Proteins Recycling Renal tubule structure Role Septate Severity of illness Signal Pathway Signal Transduction Testing Work comparative effective therapy extracellular genetic approach in vivo insight knock-down migration mouse model mutant nephrogenesis new therapeutic target polycystic kidney disease 1 protein public health relevance receptor research study response small molecule small molecule inhibitor therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common life threatening disease characterized by progressive renal tubules dilatation, bilateral formation and expansion of multiple septate fluid-filled cysts that increasinly compress the renal parenchyma, thus altering the kidney architecture and gradually impairing organ function. To date there is no cure for ADPKD, which remains a main cause of end stage renal disease. Mechanisms underlying ADPKD pathogenesis are complex and not completely understood. The disease is caused by germline mutations in the PKD1 or PKD2 genes, which code for polycystin-1 (PC1) or polycystin-2 (PC2), respectively. PC1 and PC2 intersect in various signaling pathways that converge on largely overlapping clinical manifestations. In recent years, the importance of the cilium in renal development has prompted intense investigation of the different ciliary pathways involved in cytogenesis. However, the cilia hypothesis alone is insufficient to explain the more severe cytogenetic phenotypes associated with the loss of polycystins. Cystogenic events may occur that are independent of or preceding ciliary defects, although the nature of these early triggers remains unclear. Alteration of the extracellular matrix (ECM) has long been recognized as a distinctive feature of ADPKD epithelia, and the cystogenic process is associated with increased expression of integrins. Our previous work has shown the important role of integrin-α2β1 in the survival of PC1 knockdown cells. We recently showed that integrin-β1 is a previously unrecognized key mediator of cystic pathogenesis. The working hypothesis of this application is that ECM-Integrin-PC1 interactions are important in the cystic pathways of both ciliary and non-ciliary origin. This hypothesis will b tested both in vitro and in vivo. Specifically, we will determine how Integrin-β1 functions are affected by PC1 through the comparative analysis of the proteins that participate in the integrin-β1 activation pathway in normal and cystic cells, and will determine the role of integrin-β1 in te trafficking and cross-activation of the EGF receptor pathway in cell depleted of PC1. To test the role of integrin-β1 in renal cytogenesis from ciliary defects we will analyze the effects of the deletion of integrin-β1 in genetic models of renal cystic disease that allow the conditional deletion of Pkd1, IFT20, and IFT88. Finally, we will examine the function of integrin-β1 on disease progression and the possibility to ameliorate the cystic phenotype using a small molecule to target integrin-α2β1. The results of these studies will provide insights on the function of integrin-β1 in ADPKD pathogenesis and whether cystogenic mechanisms of different genetic origin may converge onto integrin-β1 signaling pathway. Importantly, this work will determine and whether the integrin pathway can be pharmacologically targeted to slow the progression of ADPKD.