Analysis of distal conboluted tubule function in vivo

描述（由申请人提供）： 在美国，高血压影响大约25%的成年人口，并且是中风、心肌梗死、充血性心力衰竭和慢性肾病死亡的重要危险因素。肾脏的远曲小管（DCT）在钠的重吸收（主要通过氯化钠协同转运蛋白，NCC）中起关键作用，因此在血压调节中起关键作用。这是最好的说明，由疾病假性醛固酮减少症II型（PHAII），其特征是高钾血症高血压，引起的基因缺陷的调节NCC，增强其活性。PHAII可以通过噻嗪类利尿剂治疗来补救，噻嗪类利尿剂特异性抑制NCC。重要的是，噻嗪类利尿剂是大多数高血压患者的首选治疗药物，而不仅仅是PHAII患者。关于PHAII是否仅由改变的NCC活性引起，或者是否涉及其他离子通道和转运蛋白的失调，存在争议。也有证据表明NCC活性受盐皮质激素醛固酮调节。由于DCT中盐皮质激素受体水平较低，醛固酮对该肾段的生理作用尚不清楚。该建议旨在表征两种小鼠模型，以更好地了解PHAII和DCT功能。(1)在DCT中过表达NCC的小鼠的产生和分析，作为PHAII的可能模型。血压测量以及尿液和血浆电解质分析将与蛋白质组学分析联合进行。这些参数将在正常饮食和钠和钾水平已改变的饮食中进行研究。将评估噻嗪类使任何缺陷正常化的能力。(2)诱导性DCT特异性破坏盐皮质激素受体，以深入了解醛固酮在DCT功能中的作用。将生成这些小鼠，并且与目的（1）类似，将在各种饮食条件下进行血压和电解质测量。在肾脏病学和负责任的研究行为的教学计划将补充研究计划，以帮助候选人实现他的长期职业目标，在学术环境中进行独立的基础肾脏病学研究。大卫埃里森博士，在DCT生理学的领导者将指导候选人的科学发展，将输入从唐纳德博士科汉，在高血压小鼠模型的领导者。

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.