Decoding the cell-specific impact of epigenomic and alternative splicing regulation during T1D progression

Active Cooperative Agreement Awarded Last action

Award ID
U01DK143498
Recipient
Awarding agency
Obligated
$3,210,640

Award facts

Completion date 32% complete
Place of performance
New York, NY 10065, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Type 1 diabetes (T1D) is characterized by the destruction of pancreatic β cells, which respond to signals from immune cells, leading to hyperglycemia. This study aims to grasp the mechanisms influencing T1D by investigating both intrinsic β cell factors and environmental immune cell interactions. Our interdisciplinary team combines expertise in diabetes genomics, stem cell/organoid biology, and islet biology to explore these dynamics. The preliminary studies using single-cell transcriptome, single nucleus chromatin accessibility, and single nucleus (SN) multiome profiling of human pancreatic islets from healthy and T1DAFFECTED individuals. The same experiments were performed using human islets exposed to cytokines or virus simulating T1D conditions. Our integrative approaches identified gene regulatory elements (gres) at diabetes gwas. Also, we have developed tactics to differentiate human pluripotent stem cells (hpscs) into functional vascularized-immune islet organoids containing pancreatic endocrine cells, endothelial cells and immune-like cells. Here, we will apply SN- multiomic (both short and long reads RNA-SEQ and atac-SEQ) profiling, hpsc-derived organoids, crispr- based gene editing and CAS13-based gene knockdown to systematically explore the role of intrinsic and environmental signal dynamics in T1D progression and define mechanistic network controlling β cell destruction. We propose three specific aims to advance our understanding: aim 1: define the cell-specific multiomic intrinsic and environmental signatures during T1D progression. We will characterize intrinsic and environmental changes in chromatin and transcriptome profiles of islets from pre-T1D, T1D, and healthy individuals, map gene/isoform expression and chromatin accessibility, and finally integrate multi-omics data to identify cellspecific quantitative trait loci (qtls) and perform fine mapping with T1D gwas signals. Aim 2: decode the epigenomic network controlling β cell destruction during T1D progression. We will use massively parallel reporter assays to validate gres at T1D gwas loci, employ perturb-SEQ and crispr editing to validate gres, target genes, and their cellular phenotypes in isogenic hpsc-derived organoids. Aim 3: determine the impact of alternative splicing on human β cell destruction. We will validate T1D-associated alternative splicing using the xenium platform. Finally, we will examine the biological function of gene isoforms, and reverse β cell destruction in hpsc-derived organoids by targeting alternative splicing mechanisms. Our long-term goals include identifying locus-specific and network mechanisms to facilitate the development for precision medicine approaches in T1D. Key deliverables will include a comprehensive single cell triple-omic map of human islets crossing different stages of T1D progression, a molecular genetic network of intrinsic and environmental signals, and validated hpsc-derived vascularized immune-islet organoid models with T1DASSOCIATED GRE KO, gene isoform KD, etc. These findings will pave the way for the development of novel therapeutic strategies and disease progression markers for T1D.

Transactions

Action Obligated Date
Amendment $2,367,461
Amendment $0
Amendment $0
Original award $843,179

Subawards

Subrecipient Amount Awarded
Trustees Of The University Of Pennsylvania In this study, I will work with PI, Dr. Shuibing Chen, from Weill Cornell Medicine, to study the Role of “Decode the Impact of Alternative Splicing in T1D… $146,250
Subrecipient not on record The University of Michigan (Dr. Stephen Parker, MPI) will perform single nuclei RNA and ATAC (multiome) profiling along with ONT long-read sequencing of snRNA… $280,800

Quick answers

Who received award U01DK143498?

U01DK143498 was awarded to Weill Medical College Of Cornell University by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on August 1, 2025.

How much is award U01DK143498 worth?

$3,210,640 has been obligated on U01DK143498.

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