团队队伍 |
王戈林, PhD

王戈林

研究员,博士生导师

1992年于武汉老员工物学系获微生物学学士学位。1998年于武汉老员工命科学学院获得遗传学博士学位后留校任教。1999年赴美国德克萨斯大学西南医学中心从事博士后研究,于2006年晋升为讲师和美国国家卫生中心大项目共同负责人。2015年加入谷歌(Google)成立的生命科学公司Calico,致力研究和开发一类抗退行性神经疾病的药物。加入白菜网注册领取体验后的主要研究方向是了解衰老的生物学过程及抗老年病药物的筛选和研发。截至目前,已在国际权威期刊(如Cell, Nature, Nature Chemical Biology, Genes & Dev., PNAS等上发表SCI论文10余篇。


研究方向

中国及许多发达国家正在步入老年社会,而衰老是大多慢性疾病的主要风险因子。衰老过程相当复杂,可称是生命科学的一大未解之谜。目前对其分子机制研究以及与老年相关的疾病研究和新药开发的需求日渐紧迫。本课题组主要研究兴趣是通过解析小分子药物的靶向作用来揭示衰老生物过程和调节机制,同时发现新的抗肿瘤及抗老年神经退化性疾病药物,并设计和开发相应的治疗策略。本课题组重点研究方向包括:1)从系统调节NAD生物合成的角度研究衰老生物学;2) 筛选和开发新的抗退行性神经疾病的药物和抗癌的小分子,并利用这些小分子作为探针来揭示疾病的发病机理; 3)探索新的可普遍应用的方法学来鉴定细胞内药物作用靶。我们具有良好的化员工物学,生物化学,分子生物学和细胞生物学的研究基础,也得到来自结构生物学,神经学,药物化学等多学科同行们的大力协作。

科学贡献

先后发现多个很有挑战性的小分子化合物的作用机制,使我们对细胞死亡,细胞周期,神经再生等生物学问题有了新的认识。这些小分子也有潜力成为治疗神经退行性疾病或抗肿瘤的药物。谷歌成立的生命科学公司Calico购买了P7C3神经保护分子的专利许可进行药物开发。Diazonamide是全合成化学领域的著名分子,先后被两家生物医药公司进行开发,有望成为疗效好副作用小的肿瘤化疗药物。早期工作系统深入地研究了在动物发育中起重要作用的Hedgehog信号传导的调控机制,也为如何设计药物治疗其信号传导失调所引起的基底细胞癌(皮肤癌中最常见的一种)提供理论基础。

研究成果

1. 首次发现NAD合成的限速酶NAMPT是一类神经保护小分子药物P7C3的靶点, 这些研究使我们认识到提高体内NAD的生物合成可以延缓细胞死亡,有这种效果的小分子药物能发挥抗老年神经退化性疾病的作用,从而帮助相应治疗策略的设计和更优小分子的开发。相关研究成果获得一项专利。

 

图一:神经保护分子P7C3的作用机制模型
 

2. 筛选出许多诱发肿瘤细胞死亡的小分子,从中发现了第一个直接通过蛋白多聚化来激活死亡受体DR5的小分子, 这为提供安全的抗癌药物打下基础。

图二:死亡受体DR5激动剂Bioymifi的作用机制模型

 

3)发现鸟氨酸氨基转移酶(OAT)是一类天然产物抗癌药物Diazonamide的靶点,首次揭示了OAT在细胞分裂和生长中的功能。相关研究成果获得一项专利。
4)用果蝇作为动物模型研究Hedgehog信号传导,发现一系列以调节转录因子Ci/Gli为中心的重要调控机制,并首次发现新的调控因子GSK3。

 

图三:Hedgehog信号传导调控因子之一-Cos2

专利和获奖

2022  一种超碳金簇离子型化合物及其制备方法和应用。专利号:CN 113861226B

2020  新型NAMPT酶激动剂及其制备与用途。专利号:202011525254.7,PCT/CN2022/076187

2018  Chemical activators of Nicotinamide Mononucleotide Adenlyly Transferase 2 (NMNAT2) and uses thereof. Patent No.: PCT/CN2018/117723

2017  Neuroprotective compounds and methods for identifying and using same. Patent No.: US 9645139 B2

2009 Ornithine aminotransferase (OAT): a target for anticancer drugs. Patent No.: 7622289 B2 Career Development Award (Special Fellow), Leukemia & Lymphoma Society (2003-2006) 


代表性论文

1. Yao, H.#, Liu, M.#, Wang, L.#, Zu, Y.#, Wu, C.#, Li, C., Zhang, R., Lu, H., Li, F., Chen, S., Gu, X., Liu, T., Yang, M., Hua, L., Tang Y.* and Wang, G.* (2022). Discovery of small-molecule activators of nicotinamidephosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity. Cell Research 32, 570-584.

2. Xiao, K.#; Zhang, N.#; Li, F.#; Hou, D.#; Zhai, X.; Xu, W.*; Wang, G.*; Wang, H.*; Zhao, L.* (2022). Pro-oxidant response and accelerated ferroptosis caused by synergetic Au(I) release in hypercarbon-centered gold(I) cluster prodrugs. Nature Communications 13, 4669.

3. Wang, L. B.#; Liu, M. H.#; Zu, Y. M.#; Yao, H.; Wu, C.; Zhang, R. X.; Ma, W. N.; Lu, H. G.; Hua, L.; Wang, G.*; Tang, Y. F.* (2022). Optimization of NAMPT Activators to Achieve in vivo Neuroprotective Efficacy. European Journal of Medicinal Chemistry 236, 114260.

4. Gu, X.; Yao, H.; Kwon, I.*; Wang, G.* (2022). Small-molecule activation of NAMPT as a potential neuroprotective strategy, Life Medicine, https://doi.org/10.1093/lifemedi/lnac012.

5. Cai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022). The landscape of aging. Sci China Life Sci 65, https://doi.org/10.1007/s11427-022-2161-3

6. Lei, X. Q.; Li, Y. H.; Lai, Y.; Hu, S. K.; Qi, C.; Wang, G.*; Tang, Y. F.* (2021). Strain-Driven Dyotropic Rearrangement: A Unified Ring-Expansion Approach to α-Methylene-γ-butyrolactones. Angew. Chem. Int. Ed. 60, 4221–4230.  

7. Wang, X., Zhou, J., Qi, C., Wang, G. (2019). Establishing cell lines overexpressing DR3 to assess the apoptotic response to anti-mitotic therapeutics. J. Vis. Exp. 143, e58705, doi:10.3791/58705.

8. Qi, C., Wang, X., Shen, Z., Chen, S., Yu, H., Williams, N. and Wang, G. (2018). Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells. Cell Research 28, 544-555.

9. Wang, G.#, Han, T.#, Nijhawan, D., Theodoropoulos, P., Naidoo, J., Yadavalli, S., Mirzaei, H., Pieper, A.A., Ready, J.M. and McKnight, S.L. (2014). P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 158, 1324-1334.

10. Wang, G.*, Wang, X., Yu, H., Wei, S., Williams, N.S., Holmes, D.L., Halfmann, R., Naidoo, J., Wang, L., Li, L., Chen, S., Harran, P., Lei, X. and Wang. X. (2013). Small-molecule activation of the TRAIL Receptor DR5 in human cancer cells. (*First and co-corresponding author) Nature Chemical Biology 9, 84-89.

Commented by Stu Borman (2013). Small molecule makes cancer want to kill itself: agent is the first small molecule found to trigger death receptor on cancer-cell surfaces. Chemical & Engineering News, 91 (2): 37.

11. Wang, G., Shang, L., Burgett, A.W., Harran, P.G., Wang, X. (2007). Diazonamide toxin reveals a novel function for Ornithine Amino Transferase in mitotic cell division. PROC NAT ACAD SCI (USA) 104, 2068-2073.

12. Jia, J.#, Amanai, K.#, Wang, G.#, Tang, J., Wang, B., Jiang, J. (2002). Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 416, 548-552.

13. Wang, G. and Jiang, J. (2004). Multiple Cos2/Ci complexes regulate Ci subcellular localization through microtubule dependent and independent mechanisms. Developmental Biology 268, 493-505.

14. Wang, G., Amanai, K., Wang, B., Jiang, J. (2000). Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of Cubitus interruptus. Genes & Development 14, 2893-2905.

15. Wang, G., Wang, B., Jiang, J. (1999). Protein Kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus. Genes & Development 13, 2828-2837.

16. Wang, G.*, Peng, Z., Shen, P. (2000). Cloning and overexpression of the tyrosinase mel gene from Pseudomonas maltophilia. (*First and corresponding author) FEMS Microbiology Letters 185, 23-27.

17. Jesús-Cortés, H.D., Xu, P., Drawbridge, J., Estill, S.J., Huntington, P., Tran, S., Britt, J., Tesla, R., Morlock, L., Naidoo, J., Melito, L.M., Wang, G., Williams, N.S., Ready, J.M., McKnight, S.L., and Pieper, A.A. (2012). Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease. PNAS 109, 17010-17015.

18. Gao, S., Wang, Q., Wang, G., Lomenick, B., Liu, J., Fan, C.W., Deng, L.W., Huang, J., Lum, L., Chen, C. (2012). The chemistry and biology of Nakiterpiosin – C-nor-D-Homos- teroids. Synlett 16, 2298-2310.

19. Zhang, W., Zhao, Y., Tong, C., Wang, G., Wang, B., Jia, J. and Jiang, J. (2005). Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Developmental Cell 8, 267-278.

20. Liu, Y., Wang, G., Zhao, R., Shen, P. and Qu, S. (2005). Microcalorimetric study on the growth of Escherichia coli HB101 effected by recombinant plasmid. ACTACHIMI- CASINICA 63, 327-331.