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Nucleophosmin Centered Diagnostics and Treatment of Ischemic Acute Kidney Injury

Award Number: R01DK118267
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: 08/20/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Nucleophosmin Centered Diagnostics and Treatment of Ischemic Acute Kidney Injury - Project Summary/Abstract We discovered that NPM1, a required Bax chaperone, promotes regulated cell death and acute kidney injury (AKI) in the ischemic human kidney. The structure-function relationships (SAR) of NPM1 and its site of interaction with Bax are unknown, limiting the development of novel drugs to prevent NPM/Bax toxicity in kidney cells that are vulnerable to ischemic injury. Our integrative, cross disciplinary strategy combines cell biology with structural and medicinal chemistry to identify the features that render NPM toxic to kidney cells and localize the NPM domain responsible for binding Bax. Using protein structural analysis with x-ray crystallography, photo-labeling and cross-linking, we will optimize a novel Bax peptide for preventing and treating ischemic AKI in high risk cardiac surgery patients. In three aims, we will: (1) Characterize NPM structural features that cause regulated renal cell death; (2) Optimize drug design to inhibit NPM:Bax interaction, and (3) Select an effective therapeutic to prevent NPM:Bax toxicity in vitro and AKI in vivo. Prior validation of NPM’s causal role in ischemic injury in the human kidney and its conserved regulation during ischemic cell death across divergent species substantially increase the likelihood of translating our novel therapeutics to the clinic. Our scientific team has the combined expertise in regulated cell death, clinical and experimental AKI, peptide and assay design, x-ray crystallography, and mass spectrometry to advance our mechanistic understanding of ischemic cell death during AKI, identify targets and novel drugs for pre-clinical study, and potentially change the standard-of care for AKI patients.


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 = $471,531 )
2025	2025	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	4/8/2025	NON-COMPETING CONTINUATION	$471,531
2025	2021	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $471,531

Issue Date FY: 2024 ( Subtotal = $506,061 )
2024	2024	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/19/2024	NON-COMPETING CONTINUATION	$506,061
														Subtotal = $506,061

Issue Date FY: 2023 ( Subtotal = $546,108 )
2023	2023	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/21/2023	COMPETING CONTINUATION	$546,108
2023	2021	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/8/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $546,108

Issue Date FY: 2021 ( Subtotal = $249,200 )
2021	2021	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CENTER PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/7/2021	NON-COMPETING CONTINUATION	$249,200
														Subtotal = $249,200

Issue Date FY: 2020 ( Subtotal = $249,200 )
2020	2020	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CENTER PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/26/2020	NON-COMPETING CONTINUATION	$249,200
														Subtotal = $249,200

Issue Date FY: 2019 ( Subtotal = $249,200 )
2019	2019	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CENTER PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/20/2019	NEW	$249,200
														Subtotal = $249,200

Grand Total All Awards = $2,271,300

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Nucleophosmin Centered Diagnostics and Treatment of Ischemic Acute Kidney Injury

Award Number: R01DK118267

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: 08/20/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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