An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery.
An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery.
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DOI：
10.1016/j.stem.2016.07.002
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发表时间：
2016-09-01
期刊：
影响因子：
23.9
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Zeng H;Guo M;Zhou T;Tan L;Chong CN;Zhang T;Dong X;Xiang JZ;Yu AS;Yue L;Qi Q;Evans T;Graumann J;Chen S
全基因组关联研究（GWAS）增加了我们对与一系列人类疾病相关的基因座的了解。然而，应用这些发现来阐明病理生理学并促进药物发现仍然具有挑战性。在这里，我们创建了同基因人类胚胎干细胞 (hESC)，其 GWAS 鉴定的 2 型糖尿病易感基因发生突变。在从这些细胞系分化而来的胰腺β样细胞中，我们发现CDKAL1、KCNQ1和KCNJ11的突变导致体外和体内葡萄糖分泌受损，这与葡萄糖稳态缺陷相一致。 CDKAL1突变型胰岛素+细胞也对糖脂毒性过敏。高内涵化学筛选确定了一种候选药物，该药物可通过抑制 FOS/JUN 通路在体外和体内挽救 CDKAL1 特异性缺陷。我们的原理验证平台方法使用同基因 hESC 对 GWAS 识别的位点进行功能评估，并鉴定可挽救基因特异性缺陷的候选药物，为代谢疾病的精准治疗铺平了道路。曾等人。报告 GWAS 的功能评估在基于等基因 hESC 的平台中确定了候选糖尿病基因。作者发现 CDKAL1、KCNQ1 和 KCNJ11 中的双等位基因突变导致体外和体内胰岛素分泌受损，并鉴定出化合物 T5224，它通过抑制 FOS/JUN 通路来挽救突变 CDKAL1 相关的胰腺 β 细胞缺陷。
Genome wide association studies (GWAS) have increased our knowledge of loci associated with a range of human diseases. However, applying such findings to elucidate pathophysiology and promote drug discovery remains challenging. Here, we created isogenic human embryonic stem cells (hESCs) with mutations in GWAS-identified susceptibility genes for type 2 diabetes. In pancreatic betalike cells differentiated from these lines, we found that mutations in CDKAL1, KCNQ1 and KCNJ11 led to impaired glucose secretion in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1 mutant insulin+ cells were also hypersensitive to glucolipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1 specific defects in vitro and in vivo by inhibiting the FOS/JUN pathway. Our approach of a proof-of-principle platform, which uses isogenic hESCs for functional evaluation of GWAS-identified loci and identification of a drug candidate that rescues gene-specific defects, paves the way for precision therapy of metabolic diseases. Zeng et al. report functional evaluation of GWAS identified candidate diabetes genes in an isogenic hESC-based platform. The authors find that biallelic mutations in CDKAL1, KCNQ1, and KCNJ11 caused impaired insulin secretion both in vitro and in vivo, and identified the compound T5224 which rescued mutant CDKAL1 associated pancreatic beta cell defects by inhibiting the FOS/JUN pathway.
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