. Type 1 diabetes (T1D) is caused by autoimmune response induced pancreatic ? cell destruction. Both intrinsic (beta cell) and environmental (immune cell) signals play critical roles in pancreatic ? cell dysfunction and death. Understanding the intrinsic and environmental network signature dynamics will facilitate dissecting the molecular mechanisms controlling T1D progression. Here, we build an interdisciplinary team with the expertise of diabetes computational and functional genomics, stem cell biology, and islet biology to systematically explore the intrinsic and environmental changes during T1D progression. In the preliminary studies, we performed single cell transcriptome (scRNA-seq) and chromatin (scATAC-seq) profiling of healthy, autoantibody positive (both non- hyperglycemia and hyperglycemia) patient islet samples, as well as a laboratory model that mimics T1D islet cell-specific signatures using human islets exposed to either cytokines or virus. In addition, we have created a platform to use isogenic human pluripotent stem cells (hPSCs)-derived pancreatic beta cells and macrophage- like cells to explore the biological function of diabetes associated genes or single nucleotide polymorphisms. Here, we will combine our expertise of diabetes computational and functional genomics and stem cell biology to systematically investigate the role of key intrinsic and environmental signal dynamics in T1D progression and establish the mechanistic network controlling pancreatic beta cell dysfunction. To achieve these goals, we propose three specific aims:
Aim 1 : Determine the cell-specific intrinsic and environmental signatures during T1D progression.
Aim 2 : Decode the cell-specific genetic regulatory network controlling T1D progression.
Aim 3 : Validate cells, genes, genetic variants, and intrinsic and environment signatures in T1D progression using an isogenic hPSC-based platform and primary T1D islets. Our key deliverables include: 1) a single-cell resolution multi-omic (scRNA-seq, scATAC-seq) map of healthy, T1D and cytokine- or CVB4 treated human islets; 2) the cell/context-specific molecular genetic (e/caQTL) network and hub signature of intrinsic and environmental signals in human pancreatic islets; 3) Isogenic hPSC- derived beta and immune cells with T1D-associated (hub) gene knockouts to validate individual or multiple genes. These results will be foundational for development of novel drugs and precision disease progression markers.

Public Health Relevance

. Both intrinsic and environmental signals contribute to type 1 diabetes progression. Here, we propose to use transcriptome (scRNA-seq) and chromatin (scATAC-seq) profiling and human pluripotent stem cell models to systematically examine the impact of intrinsic and environmental signals on human pancreatic beta cell development, function, and survival in both healthy and disease condition. Understanding the role of intrinsic and environmental signals will significantly enhance our knowledge of beta cell survival and death in type 1 diabetes, which will pave the way to the development of drugs for mutation-specific therapy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1)
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Wang, Xujing
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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