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Targeting CtBP2 to Modulate Redox-Transcriptional Programs and Prevent Renal Tubular Cell Death in AKI

Award Number: R01DK140315
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: 08/21/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Targeting CtBP2 to Modulate Redox-Transcriptional Programs and Prevent Renal Tubular Cell Death in AKI - PROJECT SUMMARY Acute kidney injury (AKI) affects over 13 million patients annually and remains without effective treatments, with significant impact on patient outcomes and healthcare burden. Identification of causal drivers of injury that are also druggable remains a critical unmet need. During AKI, proximal tubular cells undergo metabolic collapse including ATP and NAD⁺ depletion and mitochondrial dysfunction, which triggers maladaptive transcriptional programs and renal epithelial cell death. The upstream regulators that couple metabolic stress to pathogenic transcriptional states remain undefined. This proposal identifies C-terminal Binding Protein 2 (CtBP2), a redox- sensitive, NAD⁺/NADH-dependent transcriptional corepressor, as a previously unrecognized and mechanistically tractable driver of tubular injury. CtBP2 is strongly induced in injured proximal tubules in both human and murine AKI. Its genetic deletion or pharmacologic inhibition restores metabolic gene expression, preserves tubular function, and improves renal outcomes in murine AKI models. We hypothesize that CtBP2 senses redox imbalance during AKI and drives tubular injury by repressing key genes involved in NAD⁺ biosynthesis and mitochondrial metabolism. We propose to test this hypothesis in two aims: (1) define the functional impact of genetic and pharmacological CtBP2 inhibition in murine models of ischemic, nephrotoxic, and rhabdomyolysis- associated AKI, as well as in an ischemic porcine model; and (2) identify upstream regulators and downstream targets of CtBP2 using RNA sequencing, metabolomics, ChIP-sequencing and promoter-reporter assays. The significance of this work lies in defining a core injury pathway that links metabolic dysfunction to transcriptional repression and establishes CtBP2 as a novel therapeutic target in AKI. The innovation lies in targeting a redox- sensitive transcriptional regulator not previously studied in kidney disease, combined with advanced genetic models, molecular profiling approaches, and translational large-animal studies. This work is expected to establish CtBP2 as a central driver of metabolic injury in AKI and provide proof-of-concept for the future clinical development of CtBP2-targeted therapies.


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: 2026 ( Subtotal = $1,527,305 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/21/2026	NEW	$1,527,305
														Subtotal = $1,527,305

Grand Total All Awards = $1,527,305

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Targeting CtBP2 to Modulate Redox-Transcriptional Programs and Prevent Renal Tubular Cell Death in AKI

Award Number: R01DK140315

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: 08/21/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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