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The cellular and molecular mechanisms regulating renal proximal tubule.........

调节肾近曲小管的细胞和分子机制.........

基本信息

批准号：
8465608
负责人：
Kameswaran Surendran
金额：
$ 28.45万
依托单位：
SANFORD RESEARCH/USD
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8465608
关键词：
Alagille Syndrome Alleles Biological Assay Cell Cycle Cell Line Cell division Cell membrane Cell physiology Cells Child Childhood Cilia Code Congenital Abnormality Cyst Cystic Kidney Diseases Cystic kidney Development Dimensions Dysplasia End stage renal failure Epithelial Epithelial Cells Epithelium Gene Expression Profiling Gene Mutation Genes Genetic screening method Growth Hajdu-Cheney Syndrome Head and Neck Squamous Cell Carcinoma Head and neck structure Health Human Hybrids Hyperplasia Incidence Instruction Kidney Kidney Diseases Link Longevity Lung Malignant Neoplasms Methods Microarray Analysis Modeling Molecular Molecular Genetics Morphogenesis Mus Mutation Nephrons Newborn Infant Notch Signaling Pathway Papillary Pathway interactions Patients Pediatric Research Play Polycystic Kidney Diseases Processed Genes Protein Biochemistry Proteins Proximal Kidney Tubules Renal Cell Carcinoma Renal function Renal tubule structure Role Shapes Signal Transduction Signaling Pathway Gene Skin Stratification Stratified Epithelium Structure Syndrome Testing Tissues Tubular formation Tumor Suppressor Proteins Urinary tract Yeasts improved inhibitor/antagonist jagged1 protein kidney cell monolayer mouse model nephrogenesis notch protein novel prevent

项目摘要

PROJECT SUMMARY (See instructions): Congenital abnormalities of the kidney and urinary tract (CAKUT) are the leading cause of end stage renal disease among children under 5 years, with an occurrence of approximately 1 in 500 newborns. Among the several genetic mutations that have been linked to CAKUT are mutations in Notch signaling pathway genes, Jagged-1 and Notch2. Mutations in Notch pathway genes, predicted to reduce the level of Notch signaling activity, are associated with Alagille Syndrome (ALGS), one component of which is the formation of small multi-cystic, dysplastic kidneys. Recently, the Hajdu-Cheney syndrome, also involving renal cysts, is associated with mutations in Notch2. Although the Notch pathway mutations are correlated with human pediatric syndromes including smaller kidneys and renal cysts, the underlying cellular and molecular mechanisms by which Notch signaling regulates nephron formation are only beginning to be understood. The objective of this project is to improve our understanding of the cellular and molecular mechanisms regulating renal proximal tubule morphogenesis and hence to contribute to better treatment options and better management of patients suffering from CAKUT. We propose to utilize the Notch signaling pathway as a molecular handle to identify the cellular and molecular mechanisms regulating renal proximal tubule morphogenesis. We have recently identified that reducing the level of Notch signaling during kidney development in mice results in small multi-cystic, dysplastic kidneys, proving that Notch signaling plays a critical role in renal tubule morphogenesis. In aim 1 we will use the mice with Notch signaling deficient kidneys, and three renal cell lines with Notch signaling inactivation to identify the cellular processes and genes by which Notch signaling regulates renal epithelial cell division during tubule morphogenesis. Additionally, in aim2 we will identify proteins and pathways that Notch signaling interacts with in regulating renal proximal tubule morphogenesis. This will involve testing the hypothesis that mutations in the Notch pathway genes that partially inactivate Notch signaling will modify the kidney disease in Pkd2 +/- mice. It will also involve an unbiased screen for proteins that interact with the intracellular domain of Notch2. These studies will improve our understanding of the cellular and molecular mechanisms regulating renal proximal tubule morphogenesis and in general the mechanisms by which epithelia are retained as a monolayer while they divide.

项目概述（见说明）：