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Functionalizing a T1D/T2D-associated locus within an intron of GLIS3.

Award Number: F31DK137447
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Functionalizing a T1D/T2D-associated locus within an intron of GLIS3. - PROJECT SUMMARY Diabetes mellitus has been characterized since antiquity, with the first documentation of this group of disorders dating back to 1500 BC1. While many advances have been made in the field in terms of treatment, there remains no cure for diabetes. This has become increasingly problematic for both the individuals and the entire healthcare system as rates of diabetes continue to rise. It is estimated that healthcare for individuals with diabetes costs over $200 billion per year in the United States alone2. Diminishing these costs and improving treatment options for patients are just a couple of the many reasons why diabetes-related research is so critical. I will use a genetic approach to more fully understand the initiation and progression of diabetes. In this application, I highlight a method that integrates human and mouse datasets to examine the role of intragenic and intronic regions of the genome in diabetes susceptibility. One such locus of interest resides in the first intron of the GLIS3 gene and has highly significant SNPs associated with both type 1 diabetes (T1D) and type 2 diabetes (T2D). To study this Glis3T1D/T2D locus, we determined the syntenic region in mouse and deleted 1729bp to create a novel mouse model (Glis31729 mouse). I found that these mice exhibit hyperglycemia, despite increased insulin secretion and glucose-evoked Ca2+ oscillations. My overall objective for this proposal is to functionalize this locus in an effort to elucidate its role in driving diabetes. My central hypothesis for the function of this locus is that it acts as an enhancer for Glis3 in islets, and that T1D/T2D-related SNPs within the locus alter its activity. I will test this hypothesis, and thus accomplish the goals of this proposal, by pursuing the following aims: 1) evaluate the enhancer activity of the Glis3T1D/T2D locus, 2) identify the influence of T1D/T2D-associated SNPs on transcription factor binding at the Glis3T1D/T2D locus, and 3) evaluate differentially expressed (DE) genes in the Glis3 1729 mice to reveal the role of the Glis3T1D/T2D locus on altering T1D and T2D risk. With the completion of these aims, I anticipate a more complete understanding of this non-coding locus, including how it regulates gene expression and affects both type 1 and type 2 diabetes susceptibility. Additionally, I believe this proposal will provide the necessary training for me to progress as an islet biologist and prepare me for a tenure-track position at a research institution.


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 = $36,918 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/25/2024	NON-COMPETING CONTINUATION	$36,354
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/4/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $36,918

Issue Date FY: 2023 ( Subtotal = $35,074 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/18/2023	NEW	$0
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/28/2023	NEW	$35,074
														Subtotal = $35,074

Grand Total All Awards = $71,992

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Functionalizing a T1D/T2D-associated locus within an intron of GLIS3.

Award Number: F31DK137447

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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