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CELLULAR BIOLOGY OF RENAL FUNCTION AND DISEASE

肾功能和疾病的细胞生物学

基本信息

批准号：
7610935
负责人：
Dennis Brown
金额：
$ 175.47万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7610935
关键词：
AVPR2 gene Acids Actins Address Adenylate Cyclase Adrenergic Receptor Affect Albumins Animals Antibodies Apical Apoptosis Arachidonic Acids Area Award Bicarbonates Binding Biochemical Biogenesis Biological Biological Assay Biological Models Body Fluids Calcitonin Capsid Proteins Carrier Proteins Cell Cycle Cell Fractionation Cell Line Cell Proliferation Cell membrane Cell physiology Cell surface Cells Cellular biology Chloride Channels Clathrin Clear Cell Clinical Trials Collaborations Collagen Complementary DNA Complex Confocal Microscopy Cues Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cytoplasmic Tail Cytoskeleton Cytosolic Phospholipase A2 Data Degradation Pathway Development Dinoprostone Disease Down-Regulation Duct (organ) structure Educational process of instructing Endocytosis Endosomes Environment Enzyme-Linked Immunosorbent Assay Enzymes Epididymis Epithelial Epithelial Cells Epithelium Event Faculty Feedback Fertility Fertilization Fibrosis Fluorescence Resonance Energy Transfer Funding Mechanisms Future G Protein-Coupled Receptor Genes Gelsolin Gene Proteins Generations Genitourinary system Glomerular Mesangial Cell Goals Growth Growth Factor Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Head Heart Heart Diseases Heart Hypertrophy Homeostasis Hydrogen Peroxide Image In Situ In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intercalated Cell Intracellular Signaling Proteins Kidney Kidney Diseases Knockout Mice Laboratories Lasers Lead Length Life Ligands Location Lung Lysosomes Male Genital Organs Mass Spectrum Analysis Mediating Membrane Membrane Proteins Messenger RNA Microdissection Microscope Microscopy Modeling Molecular Monomeric GTP-Binding Proteins Multivesicular Body Mus National Institute of Child Health and Human Development Nature Netherlands Organ Paper Pathway interactions Phase Phospholipase A2 Phosphorylation Physiological Play Predisposition Procedures Process Production Protein Isoforms Proteins Proteomics Protons Publications Publishing Reagent Receptor Signaling Recruitment Activity Recycling Regulation Regulatory Pathway Renal function Research Role Route Sampling Screening procedure Serum Signal Pathway Signal Transduction Signaling Protein Site Sperm Maturation Staging Steroids Stimulus Stress Striated Muscles System Tail Techniques Technology Testing Time Tissues Total Internal Reflection Fluorescent Touch sensation Transgenic Mice Translating United States National Institutes of Health Upper arm Ureteral obstruction Urine Utah Variant Vas deferens structure Vasopressin Receptor Vasopressins Vesicle Viagra Work aquaporin-2 base body system cell type cytokine data sharing enzyme activity extracellular follow-up genetic regulatory protein hormone regulation human HTATIP protein human RIPK1 protein in vivo inhibitor/antagonist insight kidney cell kidney epithelial cell laser capture microdissection lectures lung tumorigenesis mRNA Expression male mesangial cell mouse model movie mutant new therapeutic target news novel overexpression oxidant stress phospholipase A2-II polymerization programs promoter protein degradation protein expression protein protein interaction protein transport receptor reproductive reproductive function response sensor success therapeutic target trafficking trans-Golgi Network uptake vacuolar H+-ATPase water channel yeast two hybrid system

项目摘要

DESCRIPTION, OVERALL (provided by applicant): Paradigm-shifting observations on aquaporin 2 (AQP2) and vasopressin receptor (V2R) trafficking, and vacuolar ATPase (V-ATPase) pH sensing and recycling have lead to new hypotheses to be addressed in this renewal. Project I will define VP-dependent and independent regulation of AQP2, and will identify proteins whose interaction with AQP2 is modified by phosphorylation to regulate trafficking. A novel role for AQP2 in regulating actin polymerization via interaction with RhoGAPS will be explored. Use of PDE5 inhibitors and statins to achieve VP-independent urine concentration will be tested as a potential strategy for future treatment of NDI. Project II will examine ligand induced conformational changes of the V2R at varying pH and tonicity using FRET techniques to dissect intra- and intermolecular protein interactions. Association of V2R with accessory proteins during internalization will be defined in cells expressing wild type and mutant V2R. Our novel observation that V2R interacts with the ESCRT protein Alix to accelerate V2R degradation will be pursued in these studies that address the regulation of body fluid homeostasis. Project III will pursue the breakthrough finding that the V-ATPase is an endosomal pH sensor by defining conformational changes in the V-ATPase tail that result in pH-dependent recruitment of small GTPases to membranes. It will identify pH sensitive residues on the luminal domains of the V-ATPase, and use albumin uptake to show relevance of the pH sensing mechanism to proximal tubule function. Project IV will elucidate downstream effectors (PKA, Epac) of soluble adenylate cyclase in modulating V-ATPase recycling and proton secretion in the epididymis, a "model" epithelium in which luminal acidic pH is critical for sperm maturation and storage. It will examine the role of cGMP-induced proton secretion in this tissue, and will address the exciting hypothesis that the V-ATPase is also an extracellular pH sensor that provides feedback control of luminal pH. These studies will allow a better understanding of male fertility, and uncover mechanisms that regulate V-ATPase in acidifying cells in general, including renal intercalated cells. The Microscopy Core B facility has been a major contributor to the success of this PPG. All projects gain considerable added value from extensive intellectual and technical collaborations that characterize our efforts to understand the relationship between cellular signaling, protein trafficking, and the responses of urogenital epithelial cells to their environment.

总体描述（由申请人提供）：