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Genetic risk and molecular characterization of Diabetic Kidney Disease

Award Number: R01DK139395
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: 04/05/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Genetic risk and molecular characterization of Diabetic Kidney Disease - Diabetic kidney disease (DKD) is the leading cause of end-stage kidney failure in the USA and is increasing in prevalence at an alarming rate worldwide with no targeted therapy available. The pathogenesis of DKD is complex, influenced by genetics and the environment. The underlying genetic susceptibilities to DKD remain poorly understood. To investigate the genetic basis of DKD, we studied diabetes-induced podocyte depletion associated with DKD susceptibility in inbred DBA/2J mice and C57BL/6J mice, well established mouse models for DKD susceptibility and resistance, respectively. We also examined the BXD recombinant inbred panel to map genetic loci (QTL) associated with podocyte number after long-term diabetes (6 months). These studies identified a genome wide significant cis-acting regulatory region for the Xor gene encoding xanthine oxidoreductase (Xdh+XO) and an important source for ROS production in diabetes. Our data show Xor expression and activity was strongly increased by diabetes in glomeruli of DBA/2J, but not C57BL/6J resistant mice. A functional role for Xor was confirmed by a significant amelioration of albuminuria, endothelial cell mtDNA oxidative stress damage and podocyte loss in diabetic DBA/2J mice co-treated with a Xor inhibitor. We hypothesize that Xors are key contributors to phenotypic consequences in diabetes, and differential Xor regulation can predispose to DKD. We used genome editing clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 to knock in the high risk Xor promoter variants in whole animals and generated B6-Xorem1 mice to comprehensively study the effects of Xor regulation and activity in diabetes. Diabetic B6-Xorem1 mice had increased diabetic kidney injury and significant podocyte depletion compared to the parental C57BL/6J strain. B6-Xorem1 mice showed increased oxidative stress and an accumulation of mitochondrial DNA damage specifically in the glomerular endothelial cells, which was prevented by a small molecule inhibitor of Xor. Therefore, differential regulation of Xor contributed to phenotypic consequences with diabetes. We also uncovered promoter XOR orthologue variants associated with high-risk for DKD in a large human cohort. Our proposed studies will advance our understanding of DKD genetics and determine the therapeutic potential for gene editing in 2 Specific Aims: 1) To edit the high risk Xor promoter variants for DKD using gene editing. 2) To interrogate the genetics of human XOR orthologues. LONG-TERM: Our proposed studies will advance our understanding of mice and human genetics for risk of diabetic complications by investigating the role of Xor promoter risk variant, ROS, glomerular endothelial injury and cell crosstalk with podocytes. The study also proposes to edit the risk variants using gene editing with the potential for a future treatment for patients at risk of DKD.


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 = $331,100 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/21/2026	NON-COMPETING CONTINUATION	$331,100
														Subtotal = $331,100

Issue Date FY: 2025 ( Subtotal = $338,000 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/4/2025	NON-COMPETING CONTINUATION	$304,201
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/21/2025	NON-COMPETING CONTINUATION	$33,799
														Subtotal = $338,000

Issue Date FY: 2024 ( Subtotal = $338,000 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/4/2024	NEW	$338,000
														Subtotal = $338,000

Grand Total All Awards = $1,007,100

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Genetic risk and molecular characterization of Diabetic Kidney Disease

Award Number: R01DK139395

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: 04/05/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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