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Analysis of distal conboluted tubule function in vivo

体内远端复合小管功能分析

基本信息

批准号：
7920597
负责人：
JAMES A MCCORMICK
金额：
$ 5.4万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7920597
关键词：
Accounting Adult Affect Aldosterone Alkalosis Animals Apical Blood Blood Pressure Breeding Cessation of life Chronic Kidney Failure Clinical Complement Congestive Heart Failure Defect Development Diet Dietary Sodium Disease Distal Distal convoluted renal tubule structure Electrolytes Enterobacteria phage P1 Cre recombinase Essential Hypertension Extracellular Fluid Future Generations Genes Goals Hormones Hypertension Hypokalemia Hypotension Ion Channel Ion Transport Kidney Maintenance Measurement Measures Mediating Mentors Metabolic Mineralocorticoid Receptor Mineralocorticoids Modeling Mus Mutation Myocardial Infarction Na(+)-K(+)-Exchanging ATPase Nephrology Nucleic Acid Regulatory Sequences Pathogenesis Patients Pharmaceutical Preparations Phenotype Physiological Physiology Plasma Play Population Potassium Proteomics Pseudohypoaldosteronism Receptor Gene Regulation Research Risk Factors Role Site Sodium Sodium Chloride Stroke Structure Symptoms Syndrome System Tamoxifen Therapeutic Thiazide Diuretics Transgenes Transgenic Mice Type II Pseudohypoaldosteronism United States Western Blotting basolateral membrane blood pressure regulation career in vivo inhibitor/antagonist insight mouse model overexpression programs promoter responsible research conduct sodium-chloride cotransporter symporter thiazide urinary

项目摘要

DESCRIPTION (provided by applicant): Hypertension affects approximately 25% of the adult population in the United States and is an important risk factor for death from stroke, myocardial infarction, congestive heart failure, and chronic kidney disease. The distal convoluted tubule (DCT) of the kidney plays a critical role in the reabsorption of sodium (primarily via the sodium chloride cotransporter, NCC) and hence in regulation of blood pressure. This is best illustrated by the disease Pseudohypoaldosteronism type II (PHAII), characterized by hyperkalemic hypertension, caused by gene defects in regulators of NCC that enhance its activity. PHAII is remediable by treatment with thiazide diuretics, which specifically inhibit NCC. Importantly, thiazide diuretics are the first therapuetic choice in the majority of hypertensive patients, not just those with PHAII. There is controversy as to whether PHAII is caused solely by altered NCC activity, or whether dysregulation of other ion channels and transporters is involved. There is also evidence that NCC activity is regulated by the mineralocorticoid hormone aldosterone. Since levels of the mineralocorticoid receptor are low in the DCT, the physiological effects of aldosterone on this kidney segment are unclear. This proposal aims to characterize two mouse models to give better insight into PHAII and DCT function. (1) Generation and analysis of mice over-expressing NCC in the DCT, as a possible model of PHAII. Blood pressure measurements, and analysis of urinary and plasma electrolytes will be performed in conjunction with proteomic analysis. These parameters will be studied on a normal diet, and on diets in which sodium and potassium levels have been modified. The ability of thiazides to normalize any defects will be assessed. (2) Inducible, DCT-specific disruption of the mineralocorticoid receptor, to gain insight into the role of aldosterone in DCT function. These mice will be generated, and similarly to aim (1), blood pressure and electrolyte measurements will be performed under various dietary conditions. A didactic program in nephrology and in the responsible conduct of research will complement the research program to assist the candidate in achieving his long term career goal of performing independent basic nephrology research in an academic setting. Dr. David Ellison, a leader in DCT physiology will mentor the candidate's scientific development, as will input from Dr. Donald Kohan, a leader in mouse models of hypertension.

描述（由申请人提供）：