# Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice

> **NIH NIH UM1** · UNIVERSITY OF PENNSYLVANIA · 2021 · $1,843,580

## Abstract

Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice
Type 2 Diabetes (T2D) is one of the fastest-growing diseases and a leading cause of death throughout the world.
A better understanding of the disease process, including characterization of both the genetic etiology and the
contribution of different cell types to disease initiation, progression and heterogeneity promises to reveal new
therapeutic targets. Large-scale genome-wide association studies (GWAS) of this common complex trait have
driven the rapid identification of hundreds of T2D-associated loci. However, the mechanism(s) through which
most of these loci influence disease susceptibility remain poorly understood. Our interdisciplinary team at Penn
brings together experts in population genetics, T2D GWAS, biostatistics, metabolic tissue biology, human cellular
disease modeling and T2D pathophysiology to tackle this critical knowledge gap. In collaboration with other
Consortium groups, we aim to accomplish the following goals.
(1) Provide the diabetes research community with a robust pipeline for mapping T2D GWAS variants to
 effector genes and target tissues.
(2) Identify new genes and biological pathways that modulate susceptibility to T2D.
(3) Define gene regulatory networks relevant to T2D with the goal of uncovering therapeutic ‘entry
 points’ for developing new treatments.
For (1), we will prioritize “candidate effector transcripts” for downstream functional analyses by integrating
multiple sources of data to gain a ‘confluence of evidence’ as to their disease relevance and tissue of action.
These sources include publically available datasets, a unique collection of internal resources from the Million
Veteran Program, and our own functional genomics (RNA-seq, ATAC-seq, chromatin conformation capture etc.)
data generated from stem cell-derived T2D relevant cell types. For (2), we will examine the biological function of
prioritized T2D-effector transcripts in human cell models of T2D-relevant tissue types using gain- and loss-of-
function methods combined with a battery of physiological, metabolic, molecular phenotyping and genomic
approaches. These studies include the use of induced pluripotent stem cell (iPSC) models for pancreatic b cells,
hepatocytes, adipocytes and skeletal muscle cells, enabling precise genetic engineering and establishment of
multiple cell types in the same genetic background. Through this process, we will identify 10 high priority
candidate effector genes, which we will advance for comprehensive in vivo analyses in conditional mutant mouse
models. For (3), we will perform network analyses through the integration of our multiple data sources to identify
molecular memberships in broader pathways and search for pathway components that are potentially amenable
for therapeutic targeting.

## Key facts

- **NIH application ID:** 10242941
- **Project number:** 5UM1DK126194-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Struan F A Grant
- **Activity code:** UM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,843,580
- **Award type:** 5
- **Project period:** 2020-08-20 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242941

## Citation

> US National Institutes of Health, RePORTER application 10242941, Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice (5UM1DK126194-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242941. Licensed CC0.

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