Friday, May 16, 2025 5/16/2025

Examining the Role of CVB in the Generation of Beta Cell Neoantigens and Targeted Approaches at Therapeutic Intervention

Award Number: R01DK132583
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Description

Examining the Role of CVB in the Generation of Beta Cell Neoantigens and Targeted Approaches at Therapeutic Intervention - Type 1 diabetes (T1D) is an autoimmune disease that results from the targeting and destruction of pancreatic islet β cells by autoreactive immune cells, including CD4+ T cells. The cellular processes that break immune tolerance in individuals genetically predisposed to autoimmunity are poorly understood. In particular, very little is known about the events that occur at the islet-immune interface that cause auto- immune targeting of β cells. While identifying β cell autoantigens is of great importance, elucidating how β cell proteins become immunogenic is crucial. Many environmental and physiologic factors associated with T1D, including Coxsackie virus B (CVB) infection, can induce endoplasmic reticulum (ER) stress/dysfunction increasing ER dysfunction and the potential for abnormal handling and post-translational modification (PTM) of proteins. The subsequent presentation of these abnormally modified proteins (neo-antigens), by antigen presenting cells (APC) to T cells breaks immune tolerance and exacerbates pathology in many diseases, including T1D. In the context of genetic susceptibility to autoimmunity and failure of peripheral tolerance, the presentation of abnormally modified proteins by antigen presenting cells (APC) to T cells initiates pathology in a number of diseases. Therefore, ER stress induced for example, by CVB infection, within β cells may generate abnormally modified proteins that act as neo-antigens for the autoimmune response in T1D. Indeed, our work demonstrates that endoplasmic reticulum (ER) stress in b cells increases cytosolic calcium Ca2+ and the activity of tissue transglutaminase 2 (tTG2), leading to PTM generation by deamidation forming neo-epitopes and increasing T cell recognition. Furthermore, we have shown that subjects with T1D have elevated frequencies of T cells that recognize deamidated neo-epitopes and that T cells with these specificities can be found in the pancreatic lymph nodes of organ donors with T1D. Hence, it is plausible that T cells that recognize deamidated epitopes, resulting from CVB triggered ER stress induced Ca2+ flux and activation of tTG2 enzymes become activated and expanded in subjects who progress to develop type 1 diabetes. Furthermore, recent work demonstrates that enterovirus family members show a strong association with islet autoimmunity in human T1D patients and a sizeable percentage of type 1 diabetic patients have prolonged/persistent enterovirus infection associated with gut mucosa inflammation. To assess the role of CVB infection in T1D progression we will define the mechanisms by which CVB infection affects ER stress-mediated PTM of β cell proteins, contributing to β cell immunogenicity in human islets in vitro, and further determine the mechanism by which CVB infection causes a break in tolerance and accelerated disease in vivo. We will also assess therapeutic strategies that impede these enzymatic mechanisms to affect T1D progression.


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 = $500,394 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/23/2025	NON-COMPETING CONTINUATION	$500,394
														Subtotal = $500,394

Issue Date FY: 2024 ( Subtotal = $614,568 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/4/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$614,568
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	3	7/3/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$717,275
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/4/2024	NON-COMPETING CONTINUATION	$0
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	7/3/2024	NON-COMPETING CONTINUATION	-$505,766
2024	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	7/3/2024	NEW	-$211,509
														Subtotal = $614,568

Issue Date FY: 2023 ( Subtotal = $505,766 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/30/2023	NON-COMPETING CONTINUATION	$505,766
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $505,766

Issue Date FY: 2022 ( Subtotal = $583,466 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/4/2022	NEW	$583,466
														Subtotal = $583,466

Grand Total All Awards = $2,204,194

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Examining the Role of CVB in the Generation of Beta Cell Neoantigens and Targeted Approaches at Therapeutic Intervention

Award Number: R01DK132583

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer