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Targeting heat shock protein 72 to improve renal function after transplantation

Award Number: R01DK123264
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: 03/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Targeting heat shock protein 72 to improve renal function after transplantation - PROJECT SUMMARY ABSTRACT Long-term allograft function tends to be poor for people who receive kidneys from deceased donors, which comprise 70% of total transplants. A key contributor to these poor outcomes is cold storage (CS) of the organs, which induces injury during preservation. Accordingly, there is an urgent need to understand the mechanisms by which CS activates molecular pathways that induce renal damage in the recipient. Our long-term goal is to identify these CS-related pathways and apply targeted therapies during CS to improve outcomes and decrease transplant-associated mortality. One of the important molecular determinants of CS-induced kidney injury is abnormal protein homeostasis. During stress, heat-shock proteins and the proteasome play a concerted role in maintaining protein homeostasis. Hsp72 is the major stress-inducible homologue of Hsc70, the cognate member of the heat-shock protein 70 family that exhibits housekeeping function in all nucleated cells and is necessary for cell survival. Importantly, Hsc70 and Hsp72 play critical roles by binding damaged proteins and recruiting the proteasome for targeted degradation, preventing the nonspecific aggregation of damaged proteins. In addition to its protective roles, Hsp72 is implicated in the pathogenesis of numerous human diseases by modulating the immune system and inflammation. Using a clinically relevant rat model of renal CS combined with transplantation, we showed that CS decreases proteasome function and impairs protein homeostasis in the transplants. How CS decreases proteasome function in the transplants is not known. We hypothesize that CS- mediated activation of HSF1 and p38MAPK mediate the upregulation of Hsp72 and phosphorylation of Rpt6, leading to proteasome dysfunction and injury after transplantation. We have preliminary data supporting this hypothesis. We have also established animal models of CS/transplantation, which mimic the clinical reality more effectively than simple CS/warm perfusion and will allow us to test our hypothesis through 3 specific aims. Aim 1: Define the mechanism of Hsp72 upregulation and its impact on proteasome dysfunction during renal CS and transplantation. Aim 2: Delineate the mechanism of Rpt6 phosphorylation/aggregation and its impact on proteasome dysfunction during renal CS and transplantation. Aim 3: Determine the therapeutic utility of the Hsp72 inhibitor HS-72 using both rat and human models of renal CS and transplantation. This project uses a clinically relevant rat kidney transplant model as well as ex vivo human kidney perfusion pump to test the effects of novel CS-based therapies (e.g., HS-72) on proteasome/renal function after transplantation. We expect to identify molecular mediators of proteasome dysfunction and renal injury following CS and transplantation. These findings would be readily translatable, such as by administering drugs targeting these pathways to the CS solution to improve transplant outcomes and reduce mortality for transplant patients with end-stage kidney disease.


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 = $429,560 )
2025	2025	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/27/2025	NON-COMPETING CONTINUATION	$429,560
														Subtotal = $429,560

Issue Date FY: 2024 ( Subtotal = $458,197 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/6/2024	NON-COMPETING CONTINUATION	$28,637
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/19/2024	NON-COMPETING CONTINUATION	$429,560
														Subtotal = $458,197

Issue Date FY: 2023 ( Subtotal = $477,289 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/19/2023	NON-COMPETING CONTINUATION	$477,289
														Subtotal = $477,289

Issue Date FY: 2022 ( Subtotal = $514,920 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/25/2022	NON-COMPETING CONTINUATION	$463,427
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/1/2022	NON-COMPETING CONTINUATION	$51,493
														Subtotal = $514,920

Issue Date FY: 2021 ( Subtotal = $514,920 )
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/12/2021	NEW	$514,920
														Subtotal = $514,920

Grand Total All Awards = $2,394,886

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Targeting heat shock protein 72 to improve renal function after transplantation

Award Number: R01DK123264

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: 03/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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