# Investigating type 1 diabetes pathogenesis using the live pancreas tissue slice platform

> **NIH NIH F31** · UNIVERSITY OF FLORIDA · 2023 · $41,883

## Abstract

Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of the insulin-producing β cells
of the pancreas. The timeline of T1D development and progression is heterogenous with diagnosis occuring at
a few years of age in some patients versus other patients having autoantibodies for years before diagnosis. In
T1D, immune dysregulation occurs leading to autoantibody production, immune cell infiltration into the islets
(insulitis), and eventual loss of β cells. The events that occur within the β cell during this time and the resulting
impacts on β cell function remain unknown. The goal of this proposal is to determine how β cells function
during the course of T1D development, particularly during the critical early, asymptomatic stages.
Understanding these functional changes within β cells or islets is critical for a complete understanding of
disease progression and for the identification of possible therapeutic targets. The overall objective of my
proposal is to use live pancreas tissue slices to explore how β cells function during T1D development,
specifically I will identify the role immune cell infiltration plays in β cell dysfunction and loss. Live pancreas
tissue slices are ideal for these studies because these samples keep the islet in its native microenvironment
and preserve the extant tissue pathologies, allowing for studies of both β cell function and immune cell
populations. I hypothesize that immune dysregulation early in T1D progression results in dysfunction of the β
cell glucose metabolism pathway primarily mediated by mitochondrial stress, resulting in MHC class I
hyperexpression and increased β cell visibility to the immune system. To test this hypothesis, live pancreas
tissue slices generated from human organ donor tissue will be used and complemented by slices made from
pancreata of mouse models of T1D. Confocal microscopy techniques will be used to determine the degree of
insulitis within the tissue while islet function is simultaneously assessed. Additional functional assessments
such as perifusion experiments followed by insulin ELISAs and gene expression will be employed to look at
function in greater detail. The first part of this proposal focuses on assessments conducted to determine the
impacts of in situ immune cells on β cell function. To gain more control over the disease timeline, particularly to
investigate the earliest stages of disease, HLA-matched T cell avatars will be introduced to control human
pancreas tissue slices, creating an insulitic environment. Disease initiation and progression will be studied
further through adoptive transfer experiments with splenocytes from NOD mouse models. Progression to T1D
will be monitored with live pancreas tissue slices being made as disease develops. Functionality assessments
and immune cell studies will be conducted as discussed above. I expect the contribution of the proposed
research will be the identification of the role that immune dysregulation plays ...

## Key facts

- **NIH application ID:** 10620116
- **Project number:** 5F31DK130607-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Mollie Kathryn Huber
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $41,883
- **Award type:** 5
- **Project period:** 2022-05-16 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620116

## Citation

> US National Institutes of Health, RePORTER application 10620116, Investigating type 1 diabetes pathogenesis using the live pancreas tissue slice platform (5F31DK130607-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10620116. Licensed CC0.

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