张二荃 博士

北京生命科学研究所高级研究员

E. Erquan Zhang, Ph.D.

Associate Investigator, NIBS, Beijing，China

Phone：010-80726688-8605

Fax： 010-80727512

E-mail：zhangerquan@nibs.ac.cn

教育经历

Education

工作经历

Professional Experience

研究概述

过去多年中我们一直在探索各种哺乳动物的昼夜节律机制和功能。在已取得的一些重要发现的基础上，我们实验室在NIBS的新阶段可以更加专注于以下三个特定的科学目标。

1. 昼夜节律时钟的“A”类影响：腺苷、ATP与ATPase

我们前期的化学筛选找到了一类可能调节昼夜节律的腺苷类似物（包括虫草素cordycepin），并证明了其生理代谢产物的靶标是新型时钟成分，即一种名为RUVBL2的AAA+ 型ATPase，其作用是负责该功能的巨型超复合物昼夜节律转录。有趣的是，我们观察到了虫草素（及其它腺苷类似物）对时钟调节的跨物种甚至跨界的影响，这表明进化上保守的机制可能隐藏在我们在实验室定期检查的现象中。一般而言，据信时钟机制由负转录/翻译反馈环（TTFL）组成，其具有相似的结构，但是在各种生物中包含不同的组分。但是，在其他物种中，包括模型植物拟南芥中的虫草素的施用，也改变了时钟相位。因此，RUVBL2可能是转录调控大复合体中仅有的少数保守成分之一，探索它的作用机制可望解析原初生物钟最古老的进化来源问题。

2. 昼夜节律时钟与睡眠的互作问题

一般人们普遍认为，打断睡眠会影响大脑内的生物钟运行。例如，人们经常抱怨说，哪怕只是轻微的睡眠干扰，他们的内在生物钟也会受到干扰。实际上，根据临床报告，在睡眠剥夺6小时后，一些激素的振荡（例如生长激素和甲状腺素T3/T4）会被抑制。我们开发出来了一套基于光纤技术应用的长时间实时检测系统，可以用来监控活体哺乳动物的脑钟，于是我们利用它来测量睡眠剥夺（sleep-deprived）和睡眠反弹（sleep-rebound）条件下的脑钟运行。出乎意料的是，我们发现睡眠剥夺或其反弹期间视交叉上核（SCN）中昼夜节律生物钟的振荡几乎没有变化。对此现象的一种解释是，可能还有其他一些大脑区域更容易受到睡眠剥夺的影响。因此，我们对了解这些区域可能位于何处，睡眠剥夺（和/或恢复）如何影响其本地钟以及可能涉及哪些生物信号感兴趣。这些研究可能有助于理解睡眠的本质基础。

3. 昼夜节律的转化医学

我们长期以来一直在关注人类时间生物学。在最近一期的《昼夜节律生物钟专辑》组稿中，我们专门配发了一篇社论，宣称“生物钟的转化医学时代已经来临”（Go Human! Circadian Translational Medicine Has Come of Age）。在本实验室的新阶段，我们计划与国内的一些医院合作，更加专注于人类时钟生物学。例如，我们最近从一项基于家庭谱系的人类遗传研究中确定了一种双突变型PER2，它会导致昼夜节律行为受到干扰。此外，据报道，老年人的时钟较弱，而我们对哺乳动物的研究表明，带有EPAS1突变体的藏族人的时钟也可能会受干扰。此外，我们目前正在设计非侵入性方法来监测人类的时钟动态和睡眠质量。

最后，我们由于近期发现了一组调节时钟相位和振幅的化合物，证明了它们有治疗潜力。我们现在的目标是与NIBS spin-off公司合作，以解决时差、轮班工作以及人类衰老的防治问题。

所有学术论文 All Publications:

https://scholar.google.com/citations?hl=en&user=x1V6G-gAAAAJ

节选发表文章 Selected Publications (since 2017):

1. Sang, D.†, Lin, K.†, Yang, Y.†, Ran, G., Li, B., Chen, C., Li, Q., Ma, Y., Lu, L., Cui, X.-Y., Liu, Z., Lv, S.-Q., Luo, M., Liu, Q., Li, Y., and Zhang, E.E.* Prolonged sleep deprivation induces a cytokine storm-like syndrome in mammals. (2023) Cell 186: 5500-5516 {Highlighted by Nature Reviews Immunology: “Sleep deprivation whips up cytokine storm”}

2. Yu, Z. and Zhang, E.E.* Disrupted circadian rhythms in the plateau pika. (2023) Trends in Neurosciences 46: 1005-1007

3. Jiang, W.†*, Jin, L.†, Ju, D.†, Lu, Z.†, Wang, C., Guo, X., Zhao, H., Shen, S., Cheng, Z., Shen, J., Zong, G., Chen, J., Li, K., Yang, L., Zhang, Z., Feng, Y., Shen, J.Z., Zhang, E.E.*, and Wan, R.* The pancreatic clock is a key determinant of pancreatic fibrosis progression and exocrine dysfunction. (2022) Science Translational Medicine 14: eabn3586 {Highlighted by Nature Reviews Gastroenterology & Hepatology: “Stopped clock promotes fibrosis in chronic pancreatitis”}

4. Liu, N.†, Tian, H.†, Yu, Z.†, Zhao, H.†, Li, W.†, Sang, D., Lin, K., Cui, Y., Liao, M., Xu, Z., Chen, C., Guo, Y., Wang, Y., Huang, H-w, Wang, J., Zhang, H., Wu, W., Huang, H., Lv, S., Guo, Z., Wang, W., Zheng, S., Wang, F., Zhang, Y.*, Cai, T.*, and Zhang, E.E.* A highland-adaptation mutation of the Epas1 protein increases its stability and disrupts the circadian clock in the plateau pika. (2022) Cell Reports 39: 110816

5. Ju, D.†, Zhang, W.†, Yan, J., Zhao, H., Li, W., Wang, J., Liao, M., Xu, Z., Wang, Z., Zhou, G., Mei, L., Hou, N., Ying, S., Cai, T., Chen, S., Xie, X., Lai, L., Tang, C., Park, N., Takahashi, J.S., Huang, N., Qi, X.*, and Zhang, E.E.* Chemical Perturbations Reveal That RUVBL2 Regulates the Circadian Phase in Mammals. (2020) Science Translational Medicine 12: eaba0769 {Featured by Editor in the issue: “Shifting clock gears”; and by Nature Reviews Drug Discovery: “Shortening jet-lag recovery”; Highlighted by Faculty of 1000 (Very Good)}

6. Peng, S.†, Xiao, W.†, Ju, D.†, Sun, B., Hou, N., Liu, Q., Wang, Y., Zhao, H., Gao, C., Zhang, S., Cao, R., Li, P., Huang, H., Ma, Y., Wang, Y., Lai, W., Ma, Z., Zhang, W., Huang, S., Wang, H., Zhang, Z., Zhao, L., Cai, T., Zhao, Y., Wang, F., Nie, Y., Zhi, G., Yang, Y.*, Zhang, E.E.*, and Huang, N.* Identification of Entacapone as a Chemical Inhibitor of FTO Mediating Metabolic Regulation Through FOXO1. (2019) Science Translational Medicine 11: eaau7116 {Featured by Editor in the issue: “The skinny on FTO”}

7. Mei, L., Fan, Y., Lv, X., Welsh, D.K., Zhan, C.*, and Zhang, E.E.* Long-term in vivo Recording of Circadian Rhythms in Brains of Freely Moving Mice. (2018) Proceedings of the National Academy of Sciences U.S.A. 115: 4276-4281 {Highlighted by Faculty of 1000 (Very Good)}

8. Wu, Y.†, Tang, D.†, Liu, N., Xiong, W., Huang, H., Li, Y., Ma, Z., Zhao, H., Chen, P., Qi, X., and Zhang, E.E.* Reciprocal Regulation between the Circadian Clock and Hypoxia Signaling at the Genome Level in Mammals. (2017) Cell Metabolism 25: 73-85 {Cover story of the issue; Featured by Science Signaling, “Daily oxygen rhythms”}

专利 Awarded Patents (since 2017):

1. Zhang, E., Qi, X., Ju, D., Zhou, G., Zhao, H., Mei, L., Wang, Z., and Liang, L. Nucleoside analogue regulating mammalian circadian rhythm. WIPO Publication # WO2018133835A1 (granted in China and Japan; pending in USA, European Union, etc; PCT priority date: 02.02.2017)

2. Zhang, E., Zhan, C., and Mei, L. A method and instrumental design for long-term and real-time recording of gene transcriptions in live animals. NIPA Application# 2017101661043 (granted in China)

受邀报告 Invited Talks (since 2017):

1. Society for Research on Biological Rhythms Biennial Meeting, Amelia Island, Florida, USA, May 2022 (Session Chair)

2. NeuroZoom Research Talks, Virtual Conference, China, October 2020

3. Society for Research on Biological Rhythms Biennial Meeting, Virtual Conference, USA, June 2020

4. Center for Circadian Biology Annual Meeting, University of California San Diego, USA, March 2020

5. Keystone Symposia on "Hypoxia: Molecules, Mechanisms and Disease", Keystone, Colorado, USA, January 2020 (Session Chair)

6. XVI Congress, European Biological Rhythm Society, Lyon, France, August 2019

7. Sapporo Symposium on Biological Rhythms, Japanese Society for Chronobiology, Sapporo, Japan, July 2018

8. ITbM Research Seminar, Nagoya University, Japan, July 2018

9. Society for Research on Biological Rhythms Biennial Meeting, Amelia Island, Florida, USA, May 2018

10. Gordon Research Conference on Chronobiology, Stowe, Vermont, USA, July 2017