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Three-Dimensional Spatial and Translational profiling of Stress Response Pathways in Type 1 Diabetes

Award Number: R03DK147504
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: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Three-Dimensional Spatial and Translational profiling of Stress Response Pathways in Type 1 Diabetes - PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) results from autoimmune destruction of the pancreatic β cells, leading to insulin deficiency and chronic hyperglycemia. Accumulating evidence suggests that β cell stress during disease progression may play an active role in amplifying this autoimmune response through the generation of non-canonical or immunogenic proteins. We and others have shown that proinflammatory cytokines (IFN-α and IFN + IL-1) activate downstream signaling pathways within the β cell and create a feedforward cycle of inflammation and endoplasmic reticulum (ER) stress. Moreover, a growing body of evidence indicates that chronic ER and oxidative stress lead to the activation of the integrated stress response (ISR), a cytoprotective mechanism that maintains cellular protein homeostasis in response to environmental and cellular stress signals. However, chronic activation of ISR may lead to dysregulation in global RNA translation and the generation of immunogenic peptides, particularly neoantigens. These, when presented within the HLA complex, can initiate autoimmunity against β cells in early T1D. Our long-term goal is to identify how distinct cytokine signatures impact or influence  cell stress pathways during different stages of T1D progression. Thus, we hypothesize that proinflammatory cytokine-mediated activation of ISR in early T1D amplifies β-cell dysfunction and immunogenicity via changes in RNA translation and increased neoantigen production and presentation. We aim to test this hypothesis by: 1) defining how proinflammatory cytokines individually and in combination selectively modulate β cell mRNA translation and production of known neoantigens and map non-canonical RNA translation (ncORF) or untranslated open reading frames (uORF) or frameshift translation to the non-canonical proteins that are actively translated during inflammatory stress in human islets and 2) 3D spatial evaluation of disease specific RNA and protein translation in intact pancreatic tissue sections of autoantibody positive (AAb+), type 1 diabetes (<1 year of duration) and age, BMI and sex-matched non-diabetic control organ donors. This research is innovative because it employs innovative multi-omics approaches to map the distinct and global effects of selected cytokines and temporally monitor their impact on islet cell RNA translation with high precision. The proposed work will significantly advance our understanding of how β cells are altered in their function, stress pathways and antigenic profile during the early stages of T1D. Results from these studies have the potential to inform the development of biomarkers and therapies aimed at preventing T1D and protecting the functional β cell mass.


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 = $178,000 )
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	4/30/2026	NEW	$0
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/29/2026	NEW	$178,000
														Subtotal = $178,000

Grand Total All Awards = $178,000

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Three-Dimensional Spatial and Translational profiling of Stress Response Pathways in Type 1 Diabetes

Award Number: R03DK147504

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: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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