# Project 1

> **NIH NIH P01** · UNIVERSITY OF FLORIDA · 2022 · $278,370

## Abstract

PROJECT SUMMARY/ABSTRACT
For many autoimmune diseases new classes of biologic therapies have proven beneficial. These novel drugs
that alleviate damaging inflammation were developed based on a deep understanding of the specific immune
proteins (predominantly cytokines or cell membrane proteins) that cause disease pathology. To date, we lack
such a sophisticated understanding of factors that cause type 1 diabetes (T1D) pathology; however, our
knowledge is evolving as new discoveries shed light on mechanisms of T1D. For example, type 1 interferons
(IFN1) are a family of cytokines that play a key role T1D where they impair β-cell function, enhance immune-
surveillance, and augment CD8+ cytolytic T cell (CTL) mediated β-cell killing. IFN1 represent a key connection
between immune dysregulation, β-cell dysfunction, genes that form disease susceptibility, and environmental
factors (i.e., danger signals) that collectively modulate T1D development. What is still lacking is a fundamental
understanding of how IFN1 responses go awry in T1D and thus what types of interventions would be useful.
This project will focus on dissecting the complex genetics of T1D to clarify mechanisms of IFN1-induced
pathogenesis. At least seven T1D risk genes are involved in IFN1 production or signaling pathways (IFIH1,
TYK2, SOCS1, STAT4, PTPN2, PTPN22, and IL10). Two of these genes, IFIH1 and TYK2, have coding
variants that are associated with T1D risk. Hence, these genes are excellent targets for genotype:phenotype
studies. IFN-induced with helicase C domain 1 (IFIH1) is a cytoplasmic protein that binds to viral RNA
structures upon infection, triggering downstream signaling to elicit IFN1 production. How IFIH1 coding variants
affect responses by β-cells or immune cells (with Project 2) to self- or viral-RNA molecules will be the focus of
Aim 1. Previous studies have identified a P1104A coding variant in TYK2 as associated with protection against
T1D. Like IFIH1 variants, this TYK2 allotype alters IFN1 signaling in immune cells and could impact IFN1
signaling in islet cells. How the TYK2 variant affects β-cell (with Project 2) or immune cell responses (with
Project 3) to IFN1 will be the focus of Aim 2. We predict that IFIH1 risk variants are excessively sensitive to
self-RNA species or short viral dsRNA. We also predict that TYK2 risk variants allow maximal IFN1 induced
signaling leading to IFN-induced β-cell failure or IFN-induced CTL effector function. We hypothesize that risk
alleles of IFIH1 and TYK2 improperly integrate responses to cellular danger signals, leading to immune
dysregulation and T1D onset. This project will utilize an extensive repository of deeply genotyped T1D and
control donor cells as well as induced pluripotent stem cells (iPSCs), to interrogate precise questions
surrounding how mechanisms of innate immune sensing and IFN1 production lead to β-cell loss in T1D.
These studies are highly synergistic with Projects 2 & 3 are will rely heavily of Cores A & ...

## Key facts

- **NIH application ID:** 10413000
- **Project number:** 5P01AI042288-24
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** CLAYTON E MATHEWS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $278,370
- **Award type:** 5
- **Project period:** 1997-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413000

## Citation

> US National Institutes of Health, RePORTER application 10413000, Project 1 (5P01AI042288-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10413000. Licensed CC0.

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