# Dissecting transcriptomics and epigenomic signatures of immune cells in type 1 diabetes

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $516,037

## Abstract

T1D is an autoimmune disease in which cytotoxic T cells attack and destroy insulin-secreting pancreatic beta
cells. The role of genetics in T1D development is evident from its clustering in families. Although genome-wide
association studies uncovered the T1D-associated single-nucleotide-polymorphisms, currently there is a large
gap in knowledge regarding the molecular processes through which genetics contributes to autoimmunity.
Specifically, because most disease-associated SNPs have been found in non-coding genomic regions, they
are thought to impact gene regulation rather than causing production of mutated proteins. Recent advances in
our understanding of nuclear organization indicate that genetic variation may impact gene regulation through
altered 3D genomic structure and reorganization of large transcriptionally coordinated regions of the genome in
the disease relevant cell type(s). However, the link between sequence variation, cellular context, 3D genome
organization, and aberrant gene expression in T1D remains largely unknown. Our overall objective is to define
the molecular hallmark of T1D-associated immune cells from human pancreatic tissues and study the utility of
such deep profiling in detecting early T1D processes. Our latest results provide the first-ever evidence of early
transcriptomics and 3D epigenomic alterations in T1D. Our hypothesis is that pathogenic immune cell subtypes
residing in pancreatic tissues in asymptomatic and clinically diagnosed phases of T1D share transcriptional
and 3D epigenomic signatures. We propose to generate the deepest-possible molecular profiling of immune
cell populations in pancreatic tissues and peripheral blood in clinically well-characterized human organ donors
collected by HPAP. Since the most accessible entity for biomarker testing, i.e. blood, is the conduit by which
major immunological traffic occurs, we will examine if immunological features of beta cell destruction can be
found in peripheral blood at asymptomatic stages of T1D. Once the molecule and epigenomic signatures of
T1D are precisely defined in pancreatic tissues, they can be used as a powerful magnet to look for the needle
in the haystack of circulating cells. Our single-cell resolution experiments will identify T1D-associated immune
cells and deregulated genes in pancreatic tissues (Aim 1). Our state-of-the-art epigenomics, imaging, and
genome engineering techniques will determine 3D genome misfolding events associated with T1D (Aim 2).
The outcomes of each Aim can dramatically expand our understanding of early disease processes. The
integration of knowledge gained in two Aims can elucidate detailed molecular mechanisms of pathogenic gene
regulation in T1D.

## Key facts

- **NIH application ID:** 10152853
- **Project number:** 1U01DK127768-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Golnaz Vahedi
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $516,037
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152853

## Citation

> US National Institutes of Health, RePORTER application 10152853, Dissecting transcriptomics and epigenomic signatures of immune cells in type 1 diabetes (1U01DK127768-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10152853. Licensed CC0.

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