# Project 2

> **NIH NIH P01** · UNIVERSITY OF FLORIDA · 2021 · $266,994

## Abstract

PROJECT SUMMARY/ABSTRACT
The development of type 1 diabetes (T1D) relies on interactions between genes imparting disease
susceptibility and environmental factors thought to contribute to aberrant immune activation and signaling
leading to a breakdown in tolerance. These complex interactions adversely affect the development and
function of the immune cells, which mediate the autoimmune destruction of insulin-producing pancreatic β-
cells. In addition to the human leukocyte antigen (HLA) region, over 50 genetic loci have been identified that
confer varying degrees of risk for T1D. However, the specific mechanisms by which these variants alter the
development and signaling events within in the immune system remain poorly characterized. Our
studies are designed to address these knowledge gaps through investigation of peripheral blood and tissues
derived from a diverse cohort of study subjects (Core B). Through these investigations, we hope to gain a
better understanding for how genetic risk variants influence responses to environmental stimuli (e.g., IFN1;
Project 1) that lead to a large degree of heterogeneity observed in the natural history and clinical
manifestations of the disease. We will test the hypothesis that a combination of susceptibility gene
variants and aberrant extrinsic growth, survival, and differentiation factors lead to a loss of T cell
tolerance in the context of T1D. We propose to conduct a series of Aims to: 1) identify the T1D-associated
cellular and phenotypic signatures in a cross-sectional cohort of subjects with T1D, their relatives at varying
degrees of risk for the disease, and controls using extensive human immunophenotyping (HIP) by flow
cytometry together with genome-wide genotyping of >974K single nucleotide polymorphisms (SNPs) and
sophisticated bioinformatics analyses (with Project 3); 2) determine the phenotypic and functional impact of
genetic risk variants and age-associated growth factors on regulatory and effector T cell function, and 3) create
T cell receptor (TCR) “avatars” with known reactivities and isogenic cellular systems to develop a “disease in a
dish” model for assessing antigen-specific T cell function. These latter studies will employ novel
tools including lentiviral expression systems, directed gene editing of human T cells, and the utilization
of unique clinical resources to address the challenge of epistatic gene interactions in humans with T1D. In
sum, data from these Aims are expected to provide essential information about the complex interactions
between genetic risk, immune signaling events, and immune cell development that impact autoimmune
disease pathogenesis. The development and utilization of these innovative platforms will expedite our ability to
identify and test novel therapeutic interventions to halt the autoimmune destruction of β-cells in T1D.

## Key facts

- **NIH application ID:** 10204935
- **Project number:** 5P01AI042288-23
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Todd Michael Brusko
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $266,994
- **Award type:** 5
- **Project period:** 1997-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10204935

## Citation

> US National Institutes of Health, RePORTER application 10204935, Project 2 (5P01AI042288-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10204935. Licensed CC0.

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