# Functional Interrogation of Type 2 Diabetes-associated Genetic Network

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $561,893

## Abstract

Abstract. Type 2 diabetes (T2D) is a polygenetic disease marked by impaired insulin secretion in pancreatic
islet cells. Although genome-wide association studies (GWAS) have identified many T2D-associated genetic
variants/genes, understanding the molecular mechanism and cellular consequence of GWAS identified hits
remains challenging. In addition, little is known about the interaction network of GWAS identified T2D
genes/variants. Recent advances in human pluripotent stem cells (hPSCs) and CRISPR-based technologies
have enabled in vitro model systems for exploring the impact of T2D-associated genes and genetic network on
islet dysfunction.
In our recent study, we generated a panel of individual isogenic KO hESCs across 20 T2D effector genes. We
systematically evaluated the impact of each KO on β cell differentiation efficiency, insulin production and
secretion, and β cell survival. We performed allelic imbalance analysis and prioritized 18 T2D associated SNPs,
two of which are located at RFX binding motifs. Furthermore, scRNA-seq analysis of human islets revealed the
decreased expression of RFX3 and RFX6 in T2D islets. Finally, qRT-PCR analysis showed decrease expression
of RFX3 and RFX6 in seven T2D-KO hESC-derived INS-GFP+ β-like cells. Here, we propose to use isogenic
hPSC-derived islet organoids and human islets to systematically evaluate the molecular cascade involving T2D
effector genes-RFX3/6-T2D variants in human islet cell generation, survival, and function under both healthy and
T2D conditions. Three aims were proposed. In Aim 1, we will establish inducible KD hESC lines to assess the
individual and synergistic effects of RFX3/6 on human islet cell generation, function, and survival. In Aim 2, we
will decode the T2D effector genes-RFX3/6 signaling cascade in human islet cell damage in T2D conditions. In
Aim 3, we will decipher the RFX3/6-T2D variants signaling cascade.
This proposal aims to systematically evaluate the molecular cascade involving T2D effect genes-RFX3/6-T2D
variants in human islet cell, generation, survival, and function. This study will establish a comprehensive pipeline
for defining the biological function of T2D effector genes, prioritizing and validating the T2D variants, finally
mapping the interactive network of T2D associated genes/variants in disease relevant tissues. This will not only
address several challenges encountered in current T2D GWAS studies, but also shedding light on new insights
into T2D disease progression.

## Key facts

- **NIH application ID:** 11073518
- **Project number:** 1R01DK142414-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Shuibing Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $561,893
- **Award type:** 1
- **Project period:** 2024-09-19 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11073518

## Citation

> US National Institutes of Health, RePORTER application 11073518, Functional Interrogation of Type 2 Diabetes-associated Genetic Network (1R01DK142414-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11073518. Licensed CC0.

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