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Decipher the Function of C2cd4a in Metabolism

Award Number: R01DK132227
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: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Decipher the Function of C2cd4a in Metabolism - Project Summary Type 2 diabetes (T2D) is caused by insulin resistance in peripheral tissues and pancreatic beta-cell dysfunction. Insulin resistance precedes beta-cell failure, and the beta-cell’s inability to keep up with the increased demand of insulin production and secretion leads to glucose intolerance and hyperglycemia. The human C2CD4B-C2CD4A-VPS13C locus harbors a pancreatic beta-cell super-enhancer, and is heavily decorated by T2D risk-associated GWAS SNPs from virtually every ethnic group studied to date. There are only ~20 publications on “C2cd4a” in PubMed, the majority of which are association studies linking this locus to human diabetes susceptibility. Through a multi-omics approach followed by functional analysis in mice, we found that beta cell-specific C2cd4a ablation impairs insulin secretion. In this proposal, through C2cd4a we provide a basis to link exercise-induced hypoglycemia and type 2 diabetes treatment. We will investigate C2cd4a-regulated beta cell function, and build a pathway centered on C2cd4a. Two Aims are envisioned: in Aim 1, we will map the repressor domain using truncated versions of human and mouse C2CD4A, and investigate the mechanism of exercise-induced hypoglycemia in beta cell-specific C2cd4a knockout mice. In Aim 2, we will solidify C2cd4a’s role in the nucleus as a transcription cofactor, acting on promoters and enhancers of key beta cell genes. We will examine the regulation of C2cd4a by a novel intergenic long noncoding RNA. These Aims will advance our understanding of C2cd4a as a human diabetes susceptibility gene, and provide a blueprint to leverage human genetics data into biological insight that will eventually benefit 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: 2026 ( Subtotal = $402,500 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/5/2025	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2025 ( Subtotal = $362,250 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/13/2024	NON-COMPETING CONTINUATION	$362,250
														Subtotal = $362,250

Issue Date FY: 2024 ( Subtotal = $385,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/15/2024	NON-COMPETING CONTINUATION	$24,062
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/15/2023	NON-COMPETING CONTINUATION	$360,938
														Subtotal = $385,000

Issue Date FY: 2023 ( Subtotal = $399,271 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/30/2022	NEW	$399,271
														Subtotal = $399,271

Grand Total All Awards = $1,549,021

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Decipher the Function of C2cd4a in Metabolism

Award Number: R01DK132227

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: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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