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Lysine Acetylation and the Regulation of Vasopressin/Aquaporin System in the Principal Cell

Award Number: R01DK128001
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: 07/06/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Lysine Acetylation and the Regulation of Vasopressin/Aquaporin System in the Principal Cell - SUMMARY Dysregulation of arginine vasopressin (AVP) and water channels, called aquaporins (AQPs), can lead to a variety of clinically-significant water-electrolyte problems, ranging from severe dehydration to low plasma sodium. The actions of AVP in the kidney are mediated via the AVP receptor 2 (AVPR2) predominantly on the kidney principal cell. The AVP-sensitive water channels, AQP2 and AQP3, promote water reabsorption to prevent dehydration. In doing so these water channels function to concentrate the urine. Based on our compelling preliminary data, this proposal focuses on the first reported modification of AQP3, lysine 282 acetylation, in the regulation of substrate permeability. Lysine acetylation is also important for gene expression and it is regulated via acetyltransferases and deacetylases (HDACs) enzymes. We recently performed a systemic review and metanalysis and determined that chronic HDAC inhibitor use, as occurs in the treatment of cancers, results in a significant >2 odds ratio of experiencing fluid-electrolyte disorders in humans. Thus, determining the functional significance of lysine acetylation in the kidney is critically important both from a physiological perspective and in understanding the clinical impact of HDAC inhibition on water-electrolyte balance. Together, our compelling preliminary data have led us to formulate the overarching hypothesis that regulation of the kidney AVPR2/AQP axis by lysine acetylation is critical in regulating urinary concentrating ability and fluid balance. This will be tested by the following two aims: Aim 1: To test the hypothesis that lysine acetylation of AQP3 increases substrate flux in the principal cell promoting urine concentration. Aim 2: To test the hypothesis that HDAC1 and HDAC2 regulate the transcription of the AVPR2/AQP axis in the principal cell. We will combine unbiased, system biology approaches with cell to whole animal experiments to close key gaps in our understanding of concentrating mechanisms in the kidney and may reveal new therapeutic avenues to treat fluid-electrolyte disorders.


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: 2025 ( Subtotal = -$4,490 )
2025	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/18/2024	NON-COMPETING CONTINUATION	-$4,490
														Subtotal = -$4,490

Issue Date FY: 2023 ( Subtotal = $222,750 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/28/2023	NON-COMPETING CONTINUATION	$222,750
														Subtotal = $222,750

Issue Date FY: 2022 ( Subtotal = $222,750 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/8/2022	NON-COMPETING CONTINUATION	$222,750
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/16/2022	NEW	$0
														Subtotal = $222,750

Issue Date FY: 2021 ( Subtotal = $222,750 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/6/2021	NEW	$222,750
														Subtotal = $222,750

Grand Total All Awards = $663,760

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Lysine Acetylation and the Regulation of Vasopressin/Aquaporin System in the Principal Cell

Award Number: R01DK128001

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: 07/06/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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