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Stem Cell and Diabetes

Genome-wide association studies (GWAS) have generated a large database of disease associated variants. However, systematic studies on the role of genetic factors are rare due to the lack of a robust, time- and cost-efficient platform. Using isogenic hPSC-based pancreatic beta-like cells, we established a high throughput platform to systematically evaluate GWAS-identified diabetes associated genes, such as KCNJ11, KCNQ1, CDKAL1, GLIS3, GATA4/GATA6, in beta cell generation, function and survival both in vitro and in vivo. By collaborating with Environmental Protection Agency (EPA), we performed the first high throughput screen on the ToxCast library using hPSC-derived beta cells and identified propargite that causes beta cell specific cell death. In response to the COVID-19 pandemic, we applied hPSC-derived beta cells to study SARS-CoV-2 infection. Thus, we use isogenic hESC-derived pancreatic cells/organoids to study the role of genetic and environmental factors in diabetes progression, which will facility understanding the genetic network controlling pancreatic beta cell defects and perform drug screening.

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We founded the Diabetes Program at WCM with the translational goal to develop precision medicine for diabetes patients. We developed pipelines combining gene targeting with organoid and humanized mouse models to systematically study diabetes associated variants using both candidate and screening approaches. Regarding the candidate approach, we build a pipeline to prioritize and determine the variant-effector transcript-tissue axis of type 2 diabetes associated variants, and apply an isogenic hPSC platform to evaluate the biological function of these variants. In term of screening approaches, we work with Illumina to lead a large consortium effort to develop hiPSCs from 500 diabetes patients with whole genome sequencing. The WGS data will be incorporated with patient clinical information to pursue precision medicine for diabetes patients.

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3D reconstruction of confocal images of INS, E-cadherin (E-Cad) and SARS-N in the autopsy pancreas sample of a COVID-19 subject, related to Figure 1. Red, SARS-N; green, INS; blue, E-Cad; gray, DAPI.


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