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Dissecting the roles of type 2 diabetes-associated variants and effector genes in islet endoplasmic reticulum stress response

Award Number: F30DK130582
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Dissecting the roles of type 2 diabetes-associated variants and effector genes in islet endoplasmic reticulum stress response - PROJECT SUMMARY Type 2 Diabetes (T2D) is a complex disease caused by both genetic and environmental factors. Genome-wide association studies (GWAS) have identified 403 association signals at 243 loci (T2D variants) that increase T2D genetic risk. Functional (epi)genomic analyses strongly suggest that non-coding T2D variants alter transcriptional regulation and target gene expression in pancreatic islets, but only ~20% of T2D variants elicit changes in islet cis-regulatory element (CRE) use or gene expression under steady state conditions. Environmental factors such as endoplasmic reticulum (ER) stress have been implicated in islet dysfunction. However, studies to date have not assessed if or how T2D variants modulate the response of islets to ER stress. I hypothesize that these T2D variants alter islet ER stress-responsive CRE use or activity and target gene expression to contribute to islet β cell dysfunction or death in T2D. In my preliminary data analysis, I have identified ER stress-responsive CREs that overlap 407 T2D variants in islets and connected these CREs to 22 putative target gene promoters using islet promoter capture Hi-C maps. In Aim 1, I will comprehensively assess the effects of T2D variants on the use or activity of ER stress-responsive CREs using chromatin accessibility quantitative trait locus (caQTL) and massively parallel reporter assays (MPRA), respectively. In Aim 2, I will determine if the putative CRE- targeted genes are required in human islet cells for their ER stress response and survival by altering their expression using CRISPR/Cas9 epigenomic editing platforms. Successful completion of these Aims will yield a functionally characterized set of T2D variants and a validated set of downstream 'T2D target genes’ that modulate islet function and survival in response to a central (patho)physiologic stressor. More broadly, I anticipate that the principles and framework I employ in this mechanistic variant-to-function project could be applied to characterize the effects of T2D variants in the context of other environmental stressors and metabolic tissues. Importantly, completion of this project will help me master current concepts and state-of-the-art techniques in genetics and functional genomics and increase my scientific communication skills through extensive opportunities to present and publish my studies. Finally, my position as an MD/PhD student at UConn Health and The Jackson Laboratory for Genomic Medicine will not only allow me to be mentored in a world- class, highly collaborative environment, but it will provide me with opportunities to continue honing my clinical skills and gain specialized experience during and after my research phase. Fulfilling my training and development plan will be a crucial step toward my future career as a physician-scientist studying the genetic and (epi)genomic mechanisms of disease-associated variants in 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 = $53,974 )
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/4/2025	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/16/2024	NON-COMPETING CONTINUATION	$52,694
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/8/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $43,216 )
2023	2023	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/7/2023	NON-COMPETING CONTINUATION	$43,216
														Subtotal = $43,216

Issue Date FY: 2022 ( Subtotal = $42,274 )
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/25/2022	NEW	$41,558
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	7/8/2022	NEW	$716
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/25/2022	NEW	$0
														Subtotal = $42,274

Grand Total All Awards = $193,438

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Dissecting the roles of type 2 diabetes-associated variants and effector genes in islet endoplasmic reticulum stress response

Award Number: F30DK130582

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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