# Multi-modal single cell analysis for investigation of T1D pathogenesis

> **NIH NIH F31** · UNIVERSITY OF FLORIDA · 2021 · $40,225

## Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease which results from β-cell specific autoreactivity coupled
with failures in immunoregulation. The inaccessibility of the pancreas from living individuals mandates that the
majority of studies examining immune cell function in T1D be derived from peripheral blood, which may not
accurately reflect events occurring in the target organ. Moreover, although >150 genomic regions are associated
with T1D risk, little is known regarding subset- and activation state-specific expression of these loci, and the
effect of risk variants on immune function. Thus, there exists a need for studies examining the molecular basis
for T1D-associated immune dysregulation in disease-relevant tissues, namely, the pancreas and pancreatic
draining lymph nodes (pLN). Additionally, while deficits in regulatory T cell (Treg) function are implicated in the
loss of tolerance to β-cell antigens seen in T1D, the underlying mechanisms are incompletely understood. My
overall goal is to identify the mechanisms by which T1D risk variants contribute to diabetogenic immune cell
phenotypes using unsupervised and supervised analysis of high parameter single-cell datasets to identify genes
and pathways which, when manipulated, will result in enhanced Treg function. The enrichment of T1D risk
variants within DNA regulatory regions implies these variants may impact candidate gene expression. Moreover,
many known candidate genes are associated with Treg activation and function. Therefore, I hypothesize that
aberrant candidate gene expression and regulation in immune cells contributes to loss of tolerance in T1D by
promoting Treg instability that can be studied mechanistically through gene-editing. The technical innovation of
this research lies in the application of high-dimensional single cell technologies in understudied tissues that are
essential to T1D pathogenesis. The theoretical innovation of this research lies in the opportunity to bridge multiple
modalities and thereby, characterize key immune cell subsets by integrating their transcriptomic, epigenomic,
and proteomic profiles. To date, a dataset comprising this information at single cell resolution does not exist for
human organ donor tissue, thus I aim to assess the genetic regulation of immune phenotypes cross-sectionally
in a human organ donor cohort. Importantly, my preliminary data indicate cell subsets expressing T1D candidate
risk genes and TH1-associated markers are overrepresented in the pLN of T1D patients. Currently, the molecular
basis for this phenotype is unclear. Therefore, I propose to discern the potential role of T1D risk variants in
promoting proinflammatory over regulatory T cell phenotypes by performing single cell RNA-sequencing (scRNA-
seq) and scATAC-seq. Lastly, while T1D candidate genes are thought to impact Treg function, I propose to
model this in an antigen specific context, as these cells likely represent a more efficacious cell therapy product
as compa...

## Key facts

- **NIH application ID:** 10388620
- **Project number:** 1F31DK129004-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Leeana D Peters
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,225
- **Award type:** 1
- **Project period:** 2022-05-16 → 2025-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388620

## Citation

> US National Institutes of Health, RePORTER application 10388620, Multi-modal single cell analysis for investigation of T1D pathogenesis (1F31DK129004-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10388620. Licensed CC0.

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