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The role of the peri-islet extracellular matrix in islet function and the pathogenesis of type 1 diabetes

Award Number: F31DK132926
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: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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The role of the peri-islet extracellular matrix in islet function and the pathogenesis of type 1 diabetes - PROJECT SUMMARY/ABSTRACT In the pancreas the islet is surrounded by a specialized protein scaffold called the extracellular matrix (ECM) that regulates cell survival and insulin secretion. The ECM surrounding the islet consists mainly of laminin-10 and type IV collagen (COL IV) which provide mechanical and biochemical cues to the β-cells. During the onset of T1D, immune cells infiltrate the pancreas and the peri-islet ECM is degraded, leading to β-cell death. While changes to the peri-islet ECM have been well documented in T1D, the role of these ECM changes to T1D pathogenesis are largely unknown. Changes to ECM stiffness have been correlated to changes in insulin secretion; however, the mechanisms of mechanotransduction regulating insulin secretion have not been studied in the islet. Infiltrating immune cells also produce high levels of pro-inflammatory cytokines that cause islet dysfunction and death. While some studies have suggested that infiltrating immune cells degrade the peri-islet ECM, a recent study has shown that β-cell interactions with macrophages induces ECM remodeling by the β- cell. A role for the β-cell degrading the peri-islet ECM has not been established in T1D. Our overall goal is to determine the effect of changes in peri-islet ECM on islet function and to determine the role of autoreactive immune cells and cytokine stressed β-cells in remodeling the peri-islet ECM in T1D. We will utilize a novel reverse thermal gel scaffold functionalized with laminin-10 and COL IV with encapsulated mouse and human islets to accomplish this goal. Towards this goal we propose two specific aims: (1) Determine the effect of changes in ECM stiffness on islet function and insulin secretion dynamics; (2) Determine the role of autoreactive CD4+ and CD8+ T-cells and cytokine stressed β-cells in remodeling the peri-islet ECM in T1D. The results from this work will support a role for ECM mechanical properties in regulating islet function and will define a role for the β-cell in peri-islet ECM degradation and in the pathogenesis of T1D. The innovation of this work will provide useful insight into treating T1D and will help to improve diabetes therapies and the lives of 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 = $47,106 )
2025	2025	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/27/2024	NON-COMPETING CONTINUATION	$46,542
2025	2025	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/10/2025	NON-COMPETING CONTINUATION	$564
2025	2025	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	7/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $47,106

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/10/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $45,262 )
2023	2023	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/31/2023	NON-COMPETING CONTINUATION	$45,262
														Subtotal = $45,262

Issue Date FY: 2022 ( Subtotal = $44,320 )
2022	2022	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/10/2022	NEW	$44,320
2022	2022	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	6/10/2022	NEW	$0
														Subtotal = $44,320

Grand Total All Awards = $136,688

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The role of the peri-islet extracellular matrix in islet function and the pathogenesis of type 1 diabetes

Award Number: F31DK132926

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: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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