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Study the role and origin of hybrid insulin peptides in the pathogenesis of type 1 diabetes

Award Number: F31DK138763
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: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 12/12/2025
AWARD TERMINATION DATE: 02/26/2026

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Study the role and origin of hybrid insulin peptides in the pathogenesis of type 1 diabetes - Abstract Type 1 diabetes (T1D) is caused by an autoimmune response that targets and destroys insulin-producing beta cells in the pancreas. Despite advancements in managing T1D, identifying specific antigens critical for T1D onset has been challenging. Recent research has uncovered hybrid insulin peptides (HIPs), which induce an autoimmune CD4 T cell response and may serve as specific autoantigens in T1D. HIPs are generated when a peptide fragment of proinsulin binds to a peptide fragment from other beta cell proteins. Presence of various HIPs has been validated through mass spectrometric analyses of human and murine islet samples. Several of those identified HIPs have a known CD4 T cell that specifically targets them in human and murine disease. We consider these HIPs as disease-relevant because we not only have mass spectrometric evidence for their existence, but also immunological evidence verifying their role in disease. In this proposal, we plan to study the role of disease-relevant HIPs formed by the enzyme Cathepsin D (CatD) in the progression of diabetes in non- obese diabetic (NOD) mice, a amahor animal model used for the study of T1D. We hypothesize that a mutation of an insulin leucine residue (targeted by CatD) can effectively prevent CatD-mediated HIP formation, resulting in a reduction of disease incidence in genetically modified mice compared to wildtype mice. We will assess HIP formation by analyzing mouse islet samples using mass spectrometry, confirm HIP content through T cell assays with HIP-reactive T cell clones, and monitor mice for disease incidence and immune cell infiltration of the pancreatic islets. The researchers will also investigate the origin of another subgroup of HIPs (identified in human islets) that do not form through a CatD-mediated process. For this we apply a proteomic strategy to probe human islet samples by mass spectrometry with the objective to identify the enzyme responsible for their formation. The results of these experiments will provide a better understanding of the role of HIPs in disease onset. Furthermore, the identification of additional HIP-forming processes in human islets may lead to the discovery of a new therapeutic target, that may allow us to selectively block formation of HIPs in beta-cells. The proposed studies also offer me the opportunity to expand my understanding of several fields including immunology, proteomics, and mass spectrometry. These combined skillsets will provide me with expertise needed to study numerous diseases and pathogenic process throughout my anticipated career as independent investigator.


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 = -$3,852 )
2026	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/26/2026	TERMINATION	-$3,852
														Subtotal = -$3,852

Issue Date FY: 2025 ( Subtotal = $36,538 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/3/2025	NON-COMPETING CONTINUATION	$564
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/22/2025	NON-COMPETING CONTINUATION	$35,974
														Subtotal = $36,538

Issue Date FY: 2024 ( Subtotal = $35,974 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/1/2024	NEW	$0
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	5/17/2024	NEW	$1,280
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/1/2024	NEW	$34,694
														Subtotal = $35,974

Grand Total All Awards = $68,660

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Study the role and origin of hybrid insulin peptides in the pathogenesis of type 1 diabetes

Award Number: F31DK138763

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: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 12/12/2025

AWARD TERMINATION DATE: 02/26/2026

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