谢欣

个人信息：

谢欣 博士

研究员，国科大杭州高等研究院

浙江省杭州市西湖区象山支路1号 310012

E-mail: xxie@simm.ac.cn

教育背景：

1996.05－2002.05  美国新泽西医科和牙科大学，神经科学系，博士研究生

1991.09－1996.07 北京大学，化学系，本科生

工作经历：

2005.12－至今  中国科学院上海药物研究所，研究员，课题组长

2004.05－至今 国家新药筛选中心，历任模型建立II部主管, 副主任

2002.05－2003.06  美国新泽西医科和牙科大学神经科学系，博士后

研究方向：

1. G蛋白偶联受体（GPCR）信号通路与重大疾病（自身免疫病，代谢性疾病，肿瘤等）相关性研究及基于GPCR的新药研发

2. 小分子化合物调控干细胞命运的研究及新药研发（小分子诱导体细胞重编程及转分化）

代表性研究成果：

谢欣研究员长期从事基于G蛋白偶联受体（GPCR）和干细胞的重大疾病新机制、药物作用新靶点及生物活性新分子研究。其研究策略新颖，采用化学生物学和分子生物学结合的研究手段，利用老药、天然产物和特色小分子探针推进新靶点/新机制的研究，而其中发现的新活性分子一方面可作为工具药继续推进重大疾病的新机制研究，另一方面可以向药物先导化合物转化。近年来，谢欣课题组发现数个GPCR参与炎性疾病及脱髓鞘疾病的发生发展，作为主要发明人研发的靶向GPCR新药有两个完成一期临床研究，一个获得临床研究批件，其中两个实现转化。在化学诱导体细胞重编程方面，在国际上首次实现全化学诱导小鼠体内原位非心肌细胞向心肌细胞的重编程，并实现功能性修复。实验室也是国际上少数能实现全化学诱导iPS的实验室之一，为化学诱导体细胞重编程其在药物研发领域的应用提出新概念新方法。迄今已在Nature，Cell，Cell Research，Nature Communications等知名学刊上发表论文140余篇，他引>4500次；获授权20余项。

代表性论文：

1.Siwei Wang^#, Qing Zhang^#, Dan Lu, Youchen Fang, Xiaoci Yan, Jing Chen, Zhikan Xia, Qianting Yuan, Linhai Chen, Yangming Zhang, Fajun Nan, Xin Xie*. GPR84 regulates pulmonary inflammation by modulating neutrophil functions. Acta Pharmacologica Sinica, 2023 Aug;44(8):1665-1675.

2.Chen L^#, Yun Y^#, Guo S, Wang X, Xiong M, Zhao T, Xu T, Shen J, Xie X*, Wang K*. Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists. Journal of Medicinal Chemistry, 2023 Jun 22;66(12):7988-8010.

3.Heng Liu^#, Qing Zhang^#, Xinheng He^#, Mengting Jiang, Siwei Wang, Xiaoci Yan, Xi Cheng, Yang Liu, Fa-Jun Nan, H. Eric Xu*, Xin Xie*, Wanchao Yin*. Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84. Nature Communications, 2023 Jun 6;14(1):3271.

4.Shao-Xian Li^#, Si-Wei Wang^#, Lin-Hai Chen^#, Qing Zhang^#, Dan Lu, Jing Chen, You-Chen Fang, Min Gu, Xin Xie*, Fa-Jun Nan*. Unsymmetrical phosphodiesters as GPR84 antagonists with high blood exposure for the treatment of lung inflammation diseases. Journal of Medicinal Chemistry, 2023 Apr 27;66(8):5820-5838.

5.Mengmeng Jiang^#, Ren Guo^#, Yan Ai, Gang Wang, Peilan Tang, Xiaohui Jia, Bingqing He, Qianting Yuan, Xin Xie*. Small Molecule Drugs Promote Repopulation of Transplanted Hepatocytes by Stimulating Cell Dedifferentiation. JHEP Reports, 2023 Jan 14;5(4):100670.

6.Hongmin Cai, Youwei Xu, Shimeng Guo, Xinheng He, Jun Sun, Xin Li, Changyao Li, Wanchao Yin, Xi Cheng, Hualiang Jiang, H. Eric Xu*, Xin Xie*, Yi Jiang*. Structures of adenosine receptor A2BR bound to endogenous and synthetic agonists. Cell Discovery, 2022 Dec 28;8(1):140.

7.Ren Guo^#, Mengmeng Jiang^#, Gang Wang^#, Bing Li^#, Xiaohui Jia, Yan Ai, Shanshan Chen, Peilan Tang, Aijie Liu, Qianting Yuan, Xin Xie*. IL6 Supports Long-Term Expansion of Hepatocytes in vitro. Nature Communications, 2022 Nov 29;13(1):7345.

8.Youwen Zhuang*, Yue Wang, Bingqing He, Xinheng He, X. Edward Zhou, Shimeng Guo, Qidi Rao, Jiaqi Yang, Jinyu Liu, Qingtong Zhou, Xiaoxi Wang, Mingliang Liu, Weiyi Liu, Xiangrui Jiang, Dehua Yang, Hualiang Jiang, Jingshan Shen, Karsten Melcher, Yi Jiang, Xi Cheng, Ming-Wei Wang*, Xin Xie*, H. Eric Xu*. Molecular recognition of morphine and fentanyl by the human μ-opioid receptor. Cell, 2022, Nov 10;185(23):4361-4375.

9.Suo N, He B, Cui S, Yang Y, Wang M, Yuan Q, Xie X*. The orphan G protein-coupled receptor GPR149 is a negative regulator of myelination and remyelination. Glia. 2022 Oct;70(10):1992-2008.

10.Peiyu Xu, Sijie Huang, Shimeng Guo, Ying Yun, Xi Cheng, Xinheng He, Pengjun Cai, Yuan Lan, Hu Zhou, Hualiang Jiang, Yi Jiang*, Xin Xie*, H. Eric Xu*. Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119. Nature Structural & Molecular Biology. 2022 Sep;29(9):863-870.

11.Qing Zhang^#, Linhai Chen^#, Hui Yang^#, Youchen Fang, Siwei Wang, Min Wang, Qianting Yuan, Wei Wu, Yangming Zhang, Zhanju Liu*, Fajun Nan*, Xin Xie*. GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages. Acta Pharmacologica Sinica, 2022 Aug;43(8):2042-2054.

12.Guo S, Zhao T, Yun Y, Xie X*. Recent progress in assays for GPCR drug discovery. Am J Physiol Cell Physiol. 2022 Aug 1;323(2):C583-C594.

13.Ren Guo, Xiaohui Jia, Zhenbin Ding, Gang Wang, Mengmeng Jiang, Bing Li, Shanshan Chen, Bingqing Xia, Qing Zhang, Jian Liu, Ruting Zheng, Zhaobing Gao, Xin Xie*. Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation. Theranostics. 2022 Jul 4;12(11):5220-5236.

14.Duan J^#, Shen DD^#, Zhao T^#, Guo S^#, He X, Yin W, Xu P, Ji Y, Chen LN, Liu J, Zhang H, Liu Q, Shi Y, Cheng X, Jiang H, Eric Xu H*, Zhang Y*, Xie X*, Jiang Y*. Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors. Nature Communications, 2022 Mar 15;13(1):1364.

15.Chen LH^#, Zhang Q^#, Xiao YF, Fang YC, Xie X*, Nan FJ*. Phosphodiesters as GPR84 Antagonists for the Treatment of Ulcerative Colitis. Journal of Medicinal Chemistry, 2022 Mar 10;65(5):3991-4006.

16.Yun Y^#, Zhang C^#, Guo S^#, Liang X, Lan Y, Wang M, Zhuo N, Yin J, Liu H, Gu M, Li J, Xie X*, Nan F*. Identification of Betulinic Acid Derivatives as Potent TGR5 Agonists with Antidiabetic Effects via Humanized TGR5 H88Y Mutant Mice. Journal of Medicinal Chemistry, 2021 Aug 26;64(16):12181-12199.

17.Wang Y^#, Guo S^#, Zhuang Y^#, Yun Y^#, Xu P^#, He X, Guo J, Yin W, Xu HE*, Xie X*, Jiang Y*. Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor. Nature Communications, 2021 Aug 20;12(1):5064.

18.Wang C, Zhang YF, Guo S, Zhao Q, Zeng Y, Xie Z, Xie X*, Lu B*, Hu Y*. GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes. Journal of Medicinal Chemistry, 2021 Jan 28;64(2):941-957.

19.Chen LH, Zhang Q, Xie X*, Nan FJ*. Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists. Journal of Medicinal Chemistry, 2020 Dec 24;63(24):15399-15409.

20.Yang F, Mao C, Guo L, Lin J, Ming Q, Xiao P, Wu X, Shen Q, Guo S, Shen DD, Lu R, Zhang L, Huang S, Ping Y, Zhang C, Ma C, Zhang K, Liang X, Shen Y, Nan F, Yi F, Luca VC, Zhou J, Jiang C, Sun JP*, Xie X*, Yu X*, Zhang Y*. Structural basis of GPBAR activation and bile acid recognition. Nature. 2020 Nov;587(7834):499-504. doi: 10.1038/s41586-020-2569-1.

21.Wanzhi Tu, Yanbin Fu, Xin Xie*. RepSox, a small molecule inhibitor of the TGFβ receptor, induces brown adipogenesis and browning of white adipocytes. Acta Pharmacologica Sinica, 2019 Dec; 40(12):1523-1531.

22.Xue Cui, Yu-e Guo, Jiahui Fang, Changjie Shi, Na Suo, Ru Zhang*, Xin Xie*. Donepezil, a drug for Alzheimer’s disease, promotes oligodendrocytes generation and remyelination. Acta Pharmacologica Sinica, 2019 Nov; 40(11):1386-1393.

23.Na Suo, Yu-e Guo, Bingqing He, Haifeng Gu, Xin Xie*. Inhibition of MAPK/ERK pathway promotes oligodendrocytes generation and recovery of demyelinating diseases. Glia, 2019 Jul;67(7):1320-1332. doi: 10.1002/glia.23606. Epub 2019 Feb 28.

24.Chenwen Huang, Wanzhi Tu, Yanbin Fu, Xin Xie*. Chemical-induced cardiac reprogramming in vivo. Cell Research, 2018 Jun;28(6):686-689.

25.Haikun Song, Hexuan Li, Shimeng Guo, Yuyin Pan, Yuhua Fu, Zijian Zhou, Zhaoyang Li, Xue Wen, Xiaoli Sun, Bingqing He, Haifeng Gu, Youhong Hu, Xin Xie*, Boxun Lu*. Targeting Gpr52 Lowers Mutant HTT Levels and Rescues Huntington’s Disease-associated Phenotypes. Brain, 2018 Jun 1;141(6):1782-1798.

26.Ren Guo, Wei Tang, Qianting Yuan, Lijian Hui, Xin Wang, Xin Xie*. Chemical Cocktails Enable Hepatic Reprogramming of Mouse Fibroblasts with a Single Transcription Factor, Stem Cell Reports, 2017, Aug 8;9(2):499-512.

27.Jiali Jin, Jian Liu, Cong Chen, Zhenping Liu, Cong Jiang, Hongshang Chu, Weijuan Pan, Xinbo Wang, Lingqiang Zhang, Bin Li, Cizhong Jiang, Xin Ge, Xin Xie*, Ping Wang*. The deubiquitinase USP21 maintains the stemness of mouse embryonic stem cells via stabilization of Nanog. Nature Communications, 2016 Nov 25;7:13594.

28.Changsheng Du, Yanhui Duan, Hui Chai, Yingying Cai, Wei Wei, Jie Lv, Xin Xie*. Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination. Nature Communications, 2016 Apr 4;7:11120.

29.Yuan Long, Min Wang, Haifeng Gu, Xin Xie*. Bromodeoxyuridine promotes full-chemical induction of mouse pluripotent stem cells. Cell Research, 2015 Oct;25(10):1171-4.

30.Yanbin Fu, Chenwen Huang, Xinxiu Xu, Haifeng Gu, Youqiong Ye, Cizhong Jiang, Zilong Qiu, Xin Xie*. Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails. Cell Research, 2015 Sep;25(9):1013-24.

31.Kong X, Liu J, Li L, Yue L, Zhang L, Jiang H, Xie X*, Luo C*. Functional interplay between the RK motif and linker segment dictates Oct4-DNA recognition. Nucleic Acids Research, 2015 May 19; 43(9):4381-92.

32.Shuyong Zhang, Yuyong Ma, Jing Li, Biao Yu*, Xin Xie*. Molecular matchmaking between the popular ‘weight loss’ herb Hoodia gordonii and GPR119, a potential drug target for metabolic disorders. Proc Natl Acad Sci U S A, 2014 Oct 7;111(40):14571-6.

33.Guofang Chen, Xinxiu Xu, Lihong Zhang, Yanbin Fu, Min Wang, Haifeng Gu, Xin Xie*. Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug, promotes embryonic stem cells self-renewal and somatic cell reprogramming. Cell Research, 2014 Sep;24(9):1121-36.

34.Xiaoyuan Wei, Yueting Chen, Yongyu Xu, Yang Zan, Ru Zhang, Min Wang, Qiuhong Hua, Haifeng Gu, Fajun Nan*, Xin Xie*. Small molecule compound induces chromatin de-condensation and facilitate induced pluripotent stem cell generation. Journal of Molecular Cell Biology, 2014 Oct;6(5):409-20.

35.Yongyu Xu, Xiaoyuan Wei, Min Wang, Ru Zhang*, Yanbin Fu, Mingzhe Xing, Qiuhong Hua, Xin Xie*. Proliferation rate of somatic cells affects reprogramming efficiency. Journal of Biological Chemistry. 2013, Apr 5;288(14):9767-78.

36.Feifei Zhang, Wei Wei, Hui Chai, Xin Xie*. Aurintricarboxylic Acid Ameliorates Experimental Autoimmune Encephalomyelitis by Blocking Chemokine-mediated Pathogenic Cell Migration and Infiltration. Journal of Immunology. 2013 Feb 1;190(3):1017-25.

37.Wei Wei, Changsheng Du, Jie Lv, Guixian Zhao, Zhenxin Li, Zhiying Wu, György Haskó, Xin Xie*. Blocking A2B Adenosine Receptor alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and TH-17 Differentiation. Journal of Immunology. 2013 Jan 1;190(1):138-46.

38.Xinxiu Xu, Quan Wang, Yuan Long, Ru Zhang, Xiaoyuan Wei, Mingzhe Xing, Haifeng Gu, Xin Xie*. Stress-mediated p38 activation promotes somatic cell reprogramming. Cell Research. 2013 Jan;23(1):131-41.

39.Jie Lv, Changsheng Du, Wei Wei, Zhiying Wu, Guixian Zhao, Zhenxin Li, Xin Xie*. The antiepileptic drug valproic acid restores T cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis. Journal of Biological Chemistry.2012 Aug 17; 287(34):28656-65.

40.Chang-Sheng Du, Xin Xie*. G Protein-Coupled Receptors as Therapeutic Targets for Multiple Sclerosis. Cell Research. 2012 Jul; 22(7):1108-28.

41.Liefeng Wang, Changsheng Du, Jie Lv, Wei Wei, Ye Cui, Xin Xie*. Antiasthmatic Drugs Targeting the Cysteinyl Leukotriene Receptor 1 Alleviate Central Nervous System Inflammatory Cell Infiltration and Pathogenesis of Experimental Autoimmune Encephalomyelitis. Journal of Immunology. 2011;187(5):2336-45.

42.Quan Wang, Xinxiu Xu, Jun Li, Jing Liu, Haifeng Gu, Ru Zhang, Jiekai Chen, Yin Kuang, Jian Fei, Cong Jiang, Ping Wang, Duanqing Pei, Sheng Ding, Xin Xie*. Lithium, an anti-Psychotic Drug, Greatly Enhances the Generation of Induced Pluripotent Stem Cells. Cell Research. 2011;21(10):1424-35.

43.He X, Fang L, Wang J, Yi Y, Zhang S, Xie X*. Bryostatin-5 blocks stromal cell-derived factor-1 induced chemotaxis via desensitization and down-regulation of cell surface CXCR4 receptors. Cancer Research 2008 Nov 1; 68(21):8678-86.