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ANALYSIS OF DISTAL CONBOLUTED TUBULE FUNCTION IN VIVO

Award Number: K01DK076617
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2008
PERIOD OF PERFORMANCE END DATE: 02/28/2013

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ANALYSIS OF DISTAL CONBOLUTED TUBULE FUNCTION IN VIVO - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2012 ( Subtotal = $134,488 )
2012	2012	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/29/2012	NON-COMPETING CONTINUATION	$134,488
														Subtotal = $134,488

Issue Date FY: 2011 ( Subtotal = $134,488 )
2011	2011	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/23/2011	NON-COMPETING CONTINUATION	$134,488
														Subtotal = $134,488

Issue Date FY: 2010 ( Subtotal = $131,357 )
2010	2010	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Kidney Diseases, Urology and Hematology Research	000	3	3/1/2010	NON-COMPETING CONTINUATION	$131,357
														Subtotal = $131,357

Issue Date FY: 2009 ( Subtotal = $182,317 )
2009	2009	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Kidney Diseases, Urology and Hematology Research	000	2	3/4/2009	NON-COMPETING CONTINUATION	$128,317
2009	2009	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97239	MULTNOMAH	USA	Trans-NIH Recovery Act Research Support	001	2	9/17/2009	SUPPLEMENT FOR EXPANSION	$54,000
														Subtotal = $182,317

Issue Date FY: 2008 ( Subtotal = $125,366 )
2008	2008	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK ROAD	PORTLAND	OR	97201	MULTNOMAH	USA	Kidney Diseases, Urology and Hematology Research	000	1	3/25/2008	NEW	$125,366
														Subtotal = $125,366

Grand Total All Awards = $708,016

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ANALYSIS OF DISTAL CONBOLUTED TUBULE FUNCTION IN VIVO

Award Number: K01DK076617

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2008

PERIOD OF PERFORMANCE END DATE: 02/28/2013

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