Discovery of a drug candidate for GLIS3-associated diabetes.
Discovery of a drug candidate for GLIS3-associated diabetes.
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DOI：
10.1038/s41467-018-04918-x
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发表时间：
2018-07-11
影响因子：
16.6
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Amin S;Cook B;Zhou T;Ghazizadeh Z;Lis R;Zhang T;Khalaj M;Crespo M;Perera M;Xiang JZ;Zhu Z;Tomishima M;Liu C;Naji A;Evans T;Huangfu D;Chen S
GLIS 3突变与1型、2型和新生儿糖尿病相关，反映了该基因在胰腺β细胞生物学中的关键功能。以前试图在GLIS 3 −/− β样细胞中重现疾病相关表型的尝试一直不成功。在这里，我们开发了一种“最小组分”方案来产生晚期胰腺祖细胞（PP 2），其分化为单激素葡萄糖响应β样（PP 2-β）细胞。使用这个分化平台，我们发现GLIS 3 −/− hESC表现出分化受损，PP 2和PP 2-β细胞显著死亡，而不影响总内分泌池。此外，我们进行了高含量的化学筛选，并确定了在体外和体内挽救突变型GLIS 3相关β细胞死亡的候选药物。最后，我们发现GLIS 3的缺失通过激活TGFβ途径导致β细胞死亡。本研究建立了一种优化的定向分化方案，用于模拟人β细胞疾病，并确定了一种用于治疗广泛的GLIS 3相关糖尿病患者的候选药物。GLIS 3突变与1型、2型和新生儿糖尿病相关。在这里，作者在体外产生了单激素葡萄糖反应性胰腺β样细胞，并通过筛选鉴定了一种药物，该药物通过抑制异常激活的TGFβ途径来挽救GLIS 3突变体中的胰腺β样细胞死亡。
GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3−/− β-like cells have been unsuccessful. Here, we develop a “minimal component” protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3−/− hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients. GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes. Here, the authors generate mono-hormonal glucose-responding pancreatic β-like cells in vitro and through a screen identify a drug that rescues pancreatic β-like cell death in GLIS3 mutants by inhibiting the abnormally activated TGFβ pathway.
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影响因子：
23.9
作者：
Shi ZD;Lee K;Yang D;Amin S;Verma N;Li QV;Zhu Z;Soh CL;Kumar R;Evans T;Chen S;Huangfu D
通讯作者：
Huangfu D
影响因子：
3.7
作者：
Kang HS;Takeda Y;Jeon K;Jetten AM
通讯作者：
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影响因子：
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作者：
Li H;Gan W;Lu L;Dong X;Han X;Hu C;Yang Z;Sun L;Bao W;Li P;He M;Sun L;Wang Y;Zhu J;Ning Q;Tang Y;Zhang R;Wen J;Wang D;Zhu X;Guo K;Zuo X;Guo X;Yang H;Zhou X;DIAGRAM Consortium;AGEN-T2D Consortium;Zhang X;Qi L;Loos RJ;Hu FB;Wu T;Liu Y;Liu L;Yang Z;Hu R;Jia W;Ji L;Li Y;Lin X
通讯作者：
Lin X
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
全基因组关联研究的荟萃分析确定了东亚人 2 型糖尿病的 8 个新位点
影响因子：
30.8
作者：
Cho, Yoon Shin;Chen, Chien-Hsiun;Hu, Cheng;Long, Jirong;Ong, Rick Twee Hee;Sim, Xueling;Takeuchi, Fumihiko;Wu, Ying;Go, Min Jin;Yamauchi, Toshimasa;Chang, Yi-Cheng;Kwak, Soo Heon;Ma, Ronald C. W.;Yamamoto, Ken;Adair, Linda S.;Aung, Tin;Cai, Qiuyin;Chang, Li-Ching;Chen, Yuan-Tsong;Gao, Yutang;Hu, Frank B.;Kim, Hyung-Lae;Kim, Sangsoo;Kim, Young Jin;Lee, Jeannette Jen-Mai;Lee, Nanette R.;Li, Yun;Liu, Jian Jun;Lu, Wei;Nakamura, Jiro;Nakashima, Eitaro;Ng, Daniel Peng-Keat;Tay, Wan Ting;Tsai, Fuu-Jen;Wong, Tien Yin;Yokota, Mitsuhiro;Zheng, Wei;Zhang, Rong;Wang, Congrong;So, Wing Yee;Ohnaka, Keizo;Ikegami, Hiroshi;Hara, Kazuo;Cho, Young Min;Cho, Nam H.;Chang, Tien-Jyun;Bao, Yuqian;Hedman, Asa K.;Morris, Andrew P.;McCarthy, Mark I.;Takayanagi, Ryoichi;Park, Kyong Soo;Jia, Weiping;Chuang, Lee-Ming;Chan, Juliana C. N.;Maeda, Shiro;Kadowaki, Takashi;Lee, Jong-Young;Wu, Jer-Yuarn;Teo, Yik Ying;Tai, E. Shyong;Shu, Xiao Ou;Mohlke, Karen L.;Kato, Norihiro;Han, Bok-Ghee;Seielstad, Mark
通讯作者：
Seielstad, Mark