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STRUCTURE AND FUNCTION OF ROMK CHANNEL IN KIDNEY

Award Number: R01DK054999
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2001
PERIOD OF PERFORMANCE END DATE: 05/31/2009

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STRUCTURE AND FUNCTION OF ROMK CHANNEL IN KIDNEY - DESCRIPTION (provided by applicant): ROMK (Kir1.1) forms apical K channels in the distal nephron and collecting duct that provide the K secretory pathways for 1) K recycling necessary for NaCI absorption by the thick ascending limb and 2) K secretion by connecting duct and principal cells. Therefore, defining the function and regulation of the ROMK channels is important for understanding renal K handling and body K homeostasis. Loss-of-function mutations in ROMK cause Bartter's syndrome, a hypotensive renal salt wasting disease, that is due to loss of salt reabsorbing capacity by the thick ascending limb. We have developed the only ROMK Bartter's mouse with sufficiently high survival (>30%) to permit physiological study - and is the only mouse model of Bartter's with such high survival. We propose to continue to study the pathophysiology of mouse ROMK Bartter's to enhance our understanding of the role of ROMK in renal K handling and to suggest potential modalities for therapy of human Bartter's syndrome. We will also develop two new ROMK transgenic mice that will provide models for assessing both the specific roles of ROMK isoforms and the regulated trafficking of ROMK isoforms in native kidney cells. One of these isoforms, ROMK1, is only expressed in late distal tubule and collecting duct and has been suggested to play an important role in the regulation of renal K secretion by dietary K intake. We propose to generate a mouse deficient only in ROMK1 by selective deletion of the ROMK1-specific exon using a Cre-LoxP strategy. We hypothesize that this mouse will not have a Bartter's phenotype, but instead, have disordered K handling with increases or decreases in dietary K intake. We will also generate a ROMK1 BAC-transgenic mouse tagged with FLAG and EGFP to define ROMK trafficking in kidney epithelial cells and to determine associated proteins in the ROMK regulatory complex. These mice will also provide a resource for others interested in ROMK function in non- renal cells (Gl tract, brain, etc).


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: 2008 ( Subtotal = $332,315 )
2008	2008	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Kidney Diseases, Urology and Hematology Research	000	8	6/11/2008	NON-COMPETING CONTINUATION	$332,315
														Subtotal = $332,315

Issue Date FY: 2007 ( Subtotal = $329,459 )
2007	2007	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Kidney Diseases, Urology and Hematology Research	000	7	6/8/2007	NON-COMPETING CONTINUATION	$329,459
														Subtotal = $329,459

Issue Date FY: 2006 ( Subtotal = $329,660 )
2006	2006	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Kidney Diseases, Urology and Hematology Research	000	6	5/3/2006	NON-COMPETING CONTINUATION	$329,660
														Subtotal = $329,660

Issue Date FY: 2005 ( Subtotal = $328,007 )
2005	2005	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Kidney Diseases, Urology and Hematology Research	000	5	7/11/2005	COMPETING CONTINUATION	$328,007
														Subtotal = $328,007

Issue Date FY: 2004 ( Subtotal = $475,252 )
2004	2004	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Kidney Diseases, Urology and Hematology Research	000	4	1/8/2004	NON-COMPETING CONTINUATION	$475,252
														Subtotal = $475,252

Issue Date FY: 2003 ( Subtotal = $461,408 )
2003	2003	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Kidney Diseases, Urology and Hematology Research	000	3		NON-COMPETING CONTINUATION	$461,408
														Subtotal = $461,408

Issue Date FY: 2002 ( Subtotal = $447,970 )
2002	2002	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Kidney Diseases, Urology and Hematology Research	000	2	2/8/2002	NON-COMPETING CONTINUATION	$447,970
														Subtotal = $447,970

Issue Date FY: 2001 ( Subtotal = $464,180 )
2001	2001	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Kidney Diseases, Urology and Hematology Research	000	1	2/20/2001	NEW	$464,180
														Subtotal = $464,180

Grand Total All Awards = $3,168,251

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STRUCTURE AND FUNCTION OF ROMK CHANNEL IN KIDNEY

Award Number: R01DK054999

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2001

PERIOD OF PERFORMANCE END DATE: 05/31/2009

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