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Mechanisms Underlying the Susceptibility and Severity of Acute Kidney Injury

Award Number: R01DK114328
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: 08/15/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2023

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Mechanisms Underlying the Susceptibility and Severity of Acute Kidney Injury - PROJECT SUMMARY Acute kidney injury (AKI) remains a critical health problem worldwide. AKI patients requiring renal replacement therapy (dialysis) still have a 50-60% mortality rate. Patients survived dialysis-requiring AKI have a 28-fold increased risk of developing progressive chronic kidney disease (CKD), leading to end stage renal disease (ESRD). It is recognized that functioning nephrons respond to nephron deficits by increases in size and mass but not in number. Such a growth response is called compensatory nephron hypertrophy (CNH), which can occur in many situations in humans (e.g. surgical renal ablation due to renal trauma, tumor, congenital unilateral renal agenesis, or donating a kidney). Although kidney donors are highly selected from healthy individuals, recent studies have renewed our knowledge by increasingly documenting that kidney donors do have an increased risk of developing CKD and ESRD. Our goal is to define a previously undefined pathogenic role of CNH in determining the susceptibility and severity of AKI and in mediating accelerated development of interstitial fibrosis, a critical area in fighting AKI and CKD. We will also investigate the molecular mechanisms by which hypertrophied nephrons are sensitized to acute and chronic injury, with the long-term goal to identify molecular targets to reduce the incidence of AKI and development and/or progression of CKD to ESRD. Our central hypothesis is that CNH sensitizes nephrons to injury and initiates a cycle of nephron loss  nephron hypertrophy, consequently depleting functional nephrons at an accelerated rate, ultimately leading to ESRD. Our expected outcomes include: 1) a revised understanding of the traditionally so-called “compensatory renal hypertrophy” by demonstrating that hypertrophied nephron cells are sensitized to injury; 2) identification of the vicious cycle of nephron loss  nephron hypertrophy as a previously under-appreciated fundamental mechanism that drives progressive nephron damage; and 3) identification of additional potential new targets for desensitizing hypertrophied nephrons from ischemic AKI. The impact of our study will include: 1) establishment of the vicious cycle of nephron loss  nephron hypertrophy as an important mechanism underlying the progressive nature of many kidney diseases and documenting a deleterious aspect of CNH in sensitizing nephrons to injury; and 2) providing necessary preclinical knowledge about the molecular mechanisms by which CNH occurs and drives progressive nephron damage. This project may lead to development of novel and improved treatment by targeting specific signaling molecules to slow or even stop the vicious cycle of nephron loss  nephron hypertrophy to prevent kidney disease progression. Aim 1 will define the role of compensatory nephron hypertrophy in determining susceptibility and severity of AKI. Aim 2 will determine the mechanisms by which compensatory nephron hypertrophy sensitizes nephrons to AKI. Aim 3 will determine the mechanisms by which CNH accelerates development of renal fibrosis.


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: 2024 ( Subtotal = -$6,980 )
2024	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/13/2024	NON-COMPETING CONTINUATION	-$6,980
														Subtotal = -$6,980

Issue Date FY: 2021 ( Subtotal = $342,000 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/15/2021	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2020 ( Subtotal = $342,000 )
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/7/2020	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2019 ( Subtotal = $342,000 )
2019	2019	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/27/2019	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2018 ( Subtotal = $342,000 )
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/3/2018	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2017 ( Subtotal = $342,000 )
2017	2017	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/4/2017	NEW	$342,000
														Subtotal = $342,000

Grand Total All Awards = $1,703,020

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Mechanisms Underlying the Susceptibility and Severity of Acute Kidney Injury

Award Number: R01DK114328

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: 08/15/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2023

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