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Dissecting cell type-specific genetic programming of islet (dys)function in type 2 diabetes

Award Number: R01DK118011
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Type 2 diabetes (T2D) results from failure of pancreatic islets to secrete sufficient insulin to compensate for increased insulin resistance in peripheral tissues. Precise understanding of the molecular mechanisms underlying genetic and environmental contributions to islet failure is essential to develop new, targeted approaches to prevent and treat T2D. Endoplasmic reticulum (ER) and (gluco)lipotoxic stress responses are central (patho)physiologic processes that contribute to islet dysfunction and failure. Our overall objective in this proposal is to elucidate the genetic regulation of islet stress responses and to determine how genetic variants, including SNPs associated with T2D and other metabolic traits (T2D SNPs), modulate these responses to contribute to islet dysfunction and T2D pathogenesis. Based on previous studies and preliminary data, we hypothesize that T2D SNPs alter human islet stress responses by changing islet regulatory element (RE) use/function and expression of their target genes to contribute to islet dysfunction and T2D. In Aim 1, we will test this hypothesis by characterizing islet ER and (gluco)lipotoxic stress responses at the level of gene expression and identifying genetic variants altering human islet stress responses. For this, we will use bulk and single-cell RNA-Seq as well as computational analyses to discover response expression quantitative trait loci (reQTL). In Aim 2, we will take a complementary epigenomic approach to elucidate genetic effects on stress response regulatory element (RE) use in human islets. From the same islets as in Aim 1, we will determine the genome-wide location of REs at steady state and after exposure to stressors using the assay for transposase accessible chromatin-sequencing (ATAC-seq). Using these data, we will computationally identify transcription factors binding to these REs, identify genetic variants altering stress-responsive RE use by chromatin accessibility quantitative trait locus (caQTL) analyses, and test allelic effects on stress-responsive RE activity using massively parallel reporter assays (MPRA) in beta cell lines. Finally, we will experimentally manipulate these islet stress-responsive genes in human EndoC-ßH3 beta cells using CRISPR/Cas9 (epi)genome editing to determine their functions in beta cell proliferation, function, and survival (Aim 3). This study will provide mechanistic insight into how human genetic variation modulates these T2D-relevant stress responses in human islets. By delineating the genes and pathways that modulate islet (gluco)lipotoxic and ER stress responses and experimentally validating their effects on islet/beta cell resilience, this study will reveal novel therapeutic targets and guide strategies for subsequent studies manipulating these responses to prevent or treat islet failure and T2D.


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 = $806,343 )
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	11/21/2024	COMPETING CONTINUATION	$806,343
														Subtotal = $806,343

Issue Date FY: 2024 ( Subtotal = $732,112 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/3/2024	NON-COMPETING CONTINUATION	$45,757
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/22/2023	NON-COMPETING CONTINUATION	$686,355
														Subtotal = $732,112

Issue Date FY: 2023 ( Subtotal = $778,382 )
2023	2023	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/29/2022	NON-COMPETING CONTINUATION	$700,543
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/9/2023	NON-COMPETING CONTINUATION	$77,839
														Subtotal = $778,382

Issue Date FY: 2022 ( Subtotal = $784,967 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/12/2022	NON-COMPETING CONTINUATION	$78,498
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/24/2021	NON-COMPETING CONTINUATION	$706,469
														Subtotal = $784,967

Issue Date FY: 2021 ( Subtotal = $829,320 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/3/2020	NEW	$829,320
														Subtotal = $829,320

Grand Total All Awards = $3,931,124

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Dissecting cell type-specific genetic programming of islet (dys)function in type 2 diabetes

Award Number: R01DK118011

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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