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Posttranslational Neoantigens in Autoimmunity and Metabolism in T1D

Award Number: R01DK135052
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/25/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Posttranslational Neoantigens in Autoimmunity and Metabolism in T1D - Ongoing analyses from our laboratory and others have identified novel properties of self proteins, namely posttranslational protein modifications (PTMs) that may be identified as early proteomic and immunologic biomarkers of Type 1 diabetes as well as alter metabolic pathways. An emerging number of self proteins acquire PTMs and become targets of B and T cell autoimmune responses leading to inflammation and pathology in the pancreas. Some examples of critical modifications to self proteins include citrullination, oxidation, deamidation reactions, and isoaspartyl modification, all responses of self proteins within cells that undergo inflammatory stress. Key PTM candidates have already been identified from human beta cells and other key candidates will be identified from beta cell derived exosomes, recently identified as a peripheral marker of beta cell health. As importantly, these PTMs within cells may alter the biological properties of proteins within beta cells. In the present proposal, we will define how modified self-proteins may alter enzymatic pathways of glucose sensing and insulin secretion in the pancreatic beta cell. The proposal will utilize MultiOrdinate Spectral Analysis (MIMOSA), a technology pioneered at Yale University. MIMOSA is a major innovation that provides an internally cross-validated as well as NMR-validated, direct, rigorous, comprehensive integrated analysis of metabolic fluxes. The “multi-ordinate” aspect of MIMOSA incorporates the flow of stable isotope from metabolite to metabolite along intersecting metabolic pathways. The “mass isotopomer” aspect uses MS/MS-based ion fragmentation analysis of stable-isotope-labeled metabolites to identify the carbon-specific position of label. The significance and innovation of the present studies is in identifying pathways that may restore beta cell functions, via pharmaceutical correction of the aberrant modification, as well as link autoimmune biomarkers with pathways of beta cell dysfunction.


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 = $730,784 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/26/2024	NON-COMPETING CONTINUATION	$730,784
														Subtotal = $730,784

Issue Date FY: 2024 ( Subtotal = $730,784 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/3/2024	NON-COMPETING CONTINUATION	$73,077
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/21/2023	NON-COMPETING CONTINUATION	$657,707
														Subtotal = $730,784

Issue Date FY: 2023 ( Subtotal = $747,657 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/24/2023	NEW	$747,657
														Subtotal = $747,657

Grand Total All Awards = $2,209,225

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Posttranslational Neoantigens in Autoimmunity and Metabolism in T1D

Award Number: R01DK135052

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/25/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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