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Polycystin-1 Regulation of Galpha 12 and Integrins in Polycystic Kidney Disease

多囊肾病中多囊蛋白 1 对 Galpha 12 和整合素的调节

基本信息

批准号：
8107682
负责人：
Tianqing Kong
金额：
$ 15.77万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-20 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8107682
关键词：
Affect Architecture Autosomal Dominant Polycystic Kidney Binding Biological Assay Cell Communication Cell Culture Techniques Cell-Cell Adhesion Cell-Matrix Junction Cells Cilia Collagen Complex Confocal Microscopy Cyst Development E-Cadherin Epithelial Cells Event Focal Adhesions GTP-Binding Proteins Health Immunoprecipitation Integrins Kidney Kidney Failure Knockout Mice Laboratories Lead Length Link MDCK cell Macromolecular Complexes Mass Spectrum Analysis Modeling Morphology Mus Mutation Pathway interactions Permeability Polycystic Kidney Diseases Protein Binding Proteins Reagent Regulation Renal tubule structure Role Signal Pathway Signal Transduction Site Structure Surface Thrombin Tubular formation cell motility in vivo insight mouse model nephrogenesis novel polycystic kidney disease 1 protein protein complex scaffold treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Polycystic Kidney Disease (PKD) causes renal failure due to progressive tubular cystic expansion. Mutations of PKD1 are responsible for 85% of ADPKD (autosomal dominant PKD), and the gene product (polycystin-1, PC1) is a large complex protein. Polycystin-1 interacts with numerous proteins and is found in cilia, the junctional complex and at the basal surface. Abnormalities in PKD include alterations in cell-cell adhesion and cell-matrix interactions contributing to loss of normal tubule structure. The C terminus of PC1 interacts with G proteins, and we have identified binding of Ga12, but not Ga13 to the PC1 C terminus. Ga12 is also found in the epithelial cell junctional complex where it regulates permeability and cell-cell interactions. Preliminary studies reveal that cell attachment and migration on collagen-1 are regulated by Ga12 and a2b1 integrins, and activating Ga12 leads to cyst formation in tubulogenesis assays. In MDCK cells over expressing full length PC1, increased tubulogenesis is blocked by thrombin activation of endogenous Ga12 and leads to cyst formation. In a novel assay of activated Ga12, increasing or decreasing PC1 levels in MDCK cells significantly affects Ga12 activation. We hypothesize that PC1 regulates Ga12 and integrins to modulate cell matrix interactions, cell-cell adhesion and cell migration essential for normal tubule development. These studies will colocalize Ga12, integrins and PC1 in cultured renal epithelial cells and mouse kidney, and will identify the macromolecular complex through immunoprecipitation studies and mass spectrometry (Aim 1). Ga12 regulation of cell-cell adhesion, cell-matrix interaction and cell migration via integrins will be explored in Aim 2, and the role of PC1 in these signaling pathways will be elucidated in cell culture models. In Aim 3, the effect of PC1 on regulating Ga12/integrin signaling in tubulogenesis assays will be used to identify the role of these pathways in tubule development. The mechanisms leading to cyst development in vivo will be explored using a2 integrin knockout mice, PC1 null heterozyotes and gGT-Cre/QLa12 mice. PUBLIC HEALTH RELEVANCE: Polycystic Kidney Disease (PKD) causes renal failure due to progressive tubular cystic expansion. Normal kidney development is complex and requires coordinated events (signals) that regulate cell interactions with neighboring cells and the underlying support. In PKD, these signals are altered and lead to cyst formation. These studies will reveal new treatment strategies to correct these abnormal signals in PKD.

描述（由申请人提供）：