# Dissecting the roles of type 2 diabetes-associated variants and effector genes in islet endoplasmic reticulum stress response

> **NIH NIH F30** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $43,216

## Abstract

PROJECT SUMMARY
Type 2 Diabetes (T2D) is a complex disease caused by both genetic and environmental factors. Genome-wide
association studies (GWAS) have identified 403 association signals at 243 loci (T2D variants) that increase T2D
genetic risk. Functional (epi)genomic analyses strongly suggest that non-coding T2D variants alter transcriptional
regulation and target gene expression in pancreatic islets, but only ~20% of T2D variants elicit changes in islet
cis-regulatory element (CRE) use or gene expression under steady state conditions. Environmental factors such
as endoplasmic reticulum (ER) stress have been implicated in islet dysfunction. However, studies to date have
not assessed if or how T2D variants modulate the response of islets to ER stress. I hypothesize that these T2D
variants alter islet ER stress-responsive CRE use or activity and target gene expression to contribute to
islet β cell dysfunction or death in T2D. In my preliminary data analysis, I have identified ER stress-responsive
CREs that overlap 407 T2D variants in islets and connected these CREs to 22 putative target gene promoters
using islet promoter capture Hi-C maps. In Aim 1, I will comprehensively assess the effects of T2D variants on
the use or activity of ER stress-responsive CREs using chromatin accessibility quantitative trait locus (caQTL)
and massively parallel reporter assays (MPRA), respectively. In Aim 2, I will determine if the putative CRE-
targeted genes are required in human islet cells for their ER stress response and survival by altering their
expression using CRISPR/Cas9 epigenomic editing platforms. Successful completion of these Aims will yield a
functionally characterized set of T2D variants and a validated set of downstream 'T2D target genes’ that
modulate islet function and survival in response to a central (patho)physiologic stressor. More broadly, I
anticipate that the principles and framework I employ in this mechanistic variant-to-function project could be
applied to characterize the effects of T2D variants in the context of other environmental stressors and metabolic
tissues. Importantly, completion of this project will help me master current concepts and state-of-the-art
techniques in genetics and functional genomics and increase my scientific communication skills through
extensive opportunities to present and publish my studies. Finally, my position as an MD/PhD student at UConn
Health and The Jackson Laboratory for Genomic Medicine will not only allow me to be mentored in a world-
class, highly collaborative environment, but it will provide me with opportunities to continue honing my clinical
skills and gain specialized experience during and after my research phase. Fulfilling my training and development
plan will be a crucial step toward my future career as a physician-scientist studying the genetic and (epi)genomic
mechanisms of disease-associated variants in patients.

## Key facts

- **NIH application ID:** 10582540
- **Project number:** 5F30DK130582-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Redwan Bhuiyan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $43,216
- **Award type:** 5
- **Project period:** 2022-03-15 → 2026-03-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582540

## Citation

> US National Institutes of Health, RePORTER application 10582540, Dissecting the roles of type 2 diabetes-associated variants and effector genes in islet endoplasmic reticulum stress response (5F30DK130582-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10582540. Licensed CC0.

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