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Dynamic analysis of beta cell attacks in response to virus infection in Human pancreatic slices

Award Number: R21AI170010
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disease of unknown etiology leading to the destruction of pancreatic beta cells, which secrete insulin and regulate glucose homeostasis. The incidence of T1D has been increasing over the years, a trend inexplicable by only genetic predisposition, suggesting that environmental factors such as viruses play an important role in triggering the disease. Decades of research have provided epidemiological evidence for an association between T1D and viruses, particularly coxsackieviruses of the Enterovirus genus. Patients with T1D had higher rates of antibodies anti-CVB, viral RNA and viral capsid protein compared to non-diabetic. Studies have also shown that children who had developed islet autoantibodies had more CVB infections. Viral infection can impact beta cells through a direct cytolytic effect or by bystander activation of the immune system leading to gradual destruction. However, there is still little direct causal evidence from human pancreata that would establish a link between viral infections and T1D development. Although mouse studies have been very useful in understanding some of the mechanisms of the disease, there remain substantial gaps and differences to human pathology. Therefore, studies on Human pancreatic tissue samples become essential. Pancreas tissue slices are 150-200 µm thick sections of living human donor pancreatic tissue. They enable functional analysis of intact islets in their endogenous environment and 3D morphological assessment of the endocrine and exocrine pancreas as well as the blood vasculature, neurons and tissue resident immune cells. In preliminary studies, we have been able to culture and infect Human pancreatic slices using coxsackievirus B3 (CVB3)-GFP and identify the beta cells and tissue-resident macrophages as targets. Thus, we hypothesize that virus infections induce changes in tissue-resident macrophages which then induce T cells to attack and destroy beta cells. Aim 1 will evaluate the impact of CVB3-GFP infection on beta cells function and viability. Aim 2 will characterize tissue-resident macrophages during CVB3 infection by single cell RNA-seq. Aim 3 will examinate if the infection could lead to an immune destruction of beta cells when cocultured with HLA matched or autologous PBMCs. Aim 4 will characterize the impact of CVB3 infection on autophagy in infected Human pancreatic slices. Overall, this effort will generate a better understanding of the consequences of viral infections in the pancreas and its role in the onset of T1D.


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: 2024 ( Subtotal = $228,750 )
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	2/9/2024	NON-COMPETING CONTINUATION	$205,875
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	2	5/23/2024	NON-COMPETING CONTINUATION	$22,875
														Subtotal = $228,750

Issue Date FY: 2023 ( Subtotal = $274,500 )
2023	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	3/27/2023	NEW	$274,500
														Subtotal = $274,500

Grand Total All Awards = $503,250

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Dynamic analysis of beta cell attacks in response to virus infection in Human pancreatic slices

Award Number: R21AI170010

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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