# Transcriptional Mechanisms of Human Insulin Resistance

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $637,480

## Abstract

ABSTRACT
Insulin resistance (IR) is a sine qua non of Type 2 diabetes and a pathogenic factor in many other disease
states. The molecular basis of IR is complex, and associated with many interweaving pathways. We have
focused on nuclear mechanisms of IR, comprising the combined actions of transcription factors (TFs) and
epigenomic modifiers. In the prior funding cycle we have identified several transcriptional regulators of cellular
and tissue IR using advanced epigenomic strategies. For the upcoming cycle, we propose to shift to the study
of human IR; specifically, the identification of transcriptional mechanisms that drive the development of IR in
human adipocytes. Toward this end, we have generated chromatin state maps of primary adipocytes from
insulin resistant and sensitive subjects, leading to the identification of thousands of enhancers with differential
activity in IR. First, we will link these enhancers to their target genes using a novel mathematical model, and
then validate a number of these predictions using CRISPRi. Next, we will assess which of these enhancers
and genes show evidence of allelic imbalance, thus implying a genetic basis for their differential enrichment
and predicting SNPs responsible for this effect. A massively parallel reporter assay will further implicate
individual SNPs and TF motifs as candidates for drivers of IR, thus enabling the prediction of upstream
regulators that bind and activate the enhancers. Finally, we will validate causal SNPs using base editing in
cultured adipocytes testing their effects on target gene expression and insulin sensitivity. We will also validate
candidate upstream regulators using a combination of gain- and loss-of-function approaches in vitro and in
vivo. The key deliverable of this proposal will be the elucidation of the detailed transcriptional mechanisms
underlying noncoding variation leading to human IR.

## Key facts

- **NIH application ID:** 10337205
- **Project number:** 5R01DK102173-08
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Evan D Rosen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $637,480
- **Award type:** 5
- **Project period:** 2015-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337205

## Citation

> US National Institutes of Health, RePORTER application 10337205, Transcriptional Mechanisms of Human Insulin Resistance (5R01DK102173-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10337205. Licensed CC0.

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