dcbox小金库(中国)

张二荃 博士

北京科学生命dcbox小金库(中国)资深研究员

E. Erquan Zhang, Ph.D.

Investigator, NIBS, Beijing，China

Phone：010-80726688-8605

Fax： 010-80727512

E-mail：zhangerquan@nmamn.com

教育经历

Education

工作经历

Professional Experience

2025 –	北京科学生命研究所资深研究员
	Investigator, National Institute of Biological Sciences, Beijing, China

研究概述

过去多年中我们不断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，我们对分析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

我们长期以来不断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，我们现在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:

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

节选发表文章 Selected Publications:

1.      Zhao, H. †, Liao, M. †, Huo, R. †, He, T., Tian, H., Li, Z., Chen, C., Yu, Z., Chai, J., Song, X., Shao, R., Ying, S., Gao, W., Liu, L., Sang, D., Li, Q., Li, H., Wang, F.*, Ju, D.*, and Zhang, E.E.* Restoring circadian rhythms in the hypothalamic paraventricular nucleus reverses aging biomarkers and extends lifespan in male mice. dcbox小金库(中国), 189:2007–2023 (2026)

2.      Liao, M.†, Liu, Y.†, Xu, Z.†, Fang, M., Yu, Z., Cui, Y., Sun, Z., Huo, R., Yang, J., Huang, F., Liu, M., Zhou, Q., Song, X., Han, H., Chen, S., Xu, X., Qin, X., He, Q., Ju, D., Wang, T., Thakkar, N., Hardin, P.E., Golden, S.S., and Zhang, E.E.* The P-loop NTPase RUVBL2 is a conserved clock component across eukaryotes. Nature, 642:165–173 (2025)

3.      Yu, Z., Ran, G., Chai, J., and Zhang, E.E.* A nature-inspired HIF stabilizer derived from a highland-adaptation insertion of plateau pika Epas1 protein. dcbox小金库(中国) Reports, 43:114727 (2024)

4.      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) dcbox小金库(中国) 186: 5500-5516 {Featured by dcbox小金库(中国) “Best of 2024”}

5.      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

6.      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) dcbox小金库(中国) Reports 39: 110816

7.      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

8.      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

9.      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

10.   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) dcbox小金库(中国) Metabolism 25: 73-85

专利 Awarded Patents:

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, Japan, and USA; pending in European Union; 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 in Conferences:

1.      8^th Asian Forum on Chronobiology, Daejeon, SOUTH KOREA, June 2026 (Plenary Speaker)

2.      Society for Research on Biological Rhythms Biennial Meeting, Amelia Island, Florida, USA, May 2026 (Program Committee)

3.      11^th International Symposium on Transformative Bio-Molecules (ISTbM-11), Nagoya, JAPAN, November 2025

4.      International Institute for Integrative Sleep Medicine, WPI-IIIS, Tsukuba, JAPAN, November 2025

5.      Gordon Research Conference on Chronobiology, Barcelona, SPAIN, July 2025

6.      19^th ITMAT Annual International Symposium, University of Pennsylvania, Philadelphia, USA, October 2024

7.      Cold Spring Harbor Laboratory-Asia Conference on Sleep Mechanism & Function, Suzhou, CHINA, September 2024

8.      7^th Asian Forum on Chronobiology, Sapporo, JAPAN, August 2024 (Keynote Speaker)

9.      Society for Research on Biological Rhythms Biennial Meeting, Puerto Rico, May 2024

10.   Annual Meeting of China Sleep Research Society, Hefei, CHINA, October 2023 (Keynote Speaker)

11.   International Symposium on Circadian Rhythms in Sleep, Physiology, and Medicine, Chongqing, CHINA, October 2023 (Co-organizer)

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

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

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

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

16.   XVI Congress, European Biological Rhythm Society, Lyon, FRANCE, August 2019

17.   5^th World Congress of Chronobiology, Suzhou, CHINA, April 2019 (Co-organizer)

18.   1^st Beijing International Symposium on the Circadian Clock and Sleep Research, Beijing, CHINA, April 2019 (Co-organizer)

19.   Sapporo Symposium on Biological Rhythms, Japanese Society for Chronobiology, Sapporo, JAPAN, July 2018

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

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

22.   2^nd Asian Forum on Chronobiology, Hohhot, Inner Mongolia, CHINA, June 2017 (Co-organizer)

23.   International ChronoBiology Summer School, Peking University, Beijing, CHINA, August 2016 (Co-organizer)