張二荃 博士

北京生命科學研究所高級研究員

E. Erquan Zhang, Ph.D.

Associate Investigator, NIBS, Beijing，China

Phone：010-80726688-8605

Fax： 010-80727512

E-mail：zhangerquan@nibs.ac.cn

教育經歷

Education

工作經歷

Professional Experience

研究概述

過去多年中我們一直在探索各種哺乳動物的晝夜節律機制和功能。在已取得的一些重要發現的基礎上，我們實驗室在NIBS的新階段可以更加專注于以下三個特定的科學目標。

1. 晝夜節律時鐘的“A”類影響：腺苷、ATP與ATPase

我們前期的化學篩選找到了一類可能調節晝夜節律的腺苷類似物（包括蟲草素cordycepin），并證明了其生理代謝產物的靶標是新型時鐘成分，即一種名為RUVBL2的AAA+ 型ATPase，其作用是負責該功能的巨型超復合物晝夜節律轉錄。有趣的是，我們觀察到了蟲草素（及其它腺苷類似物）對時鐘調節的跨物種甚至跨界的影響，這表明進化上保守的機制可能隱藏在我們在實驗室定期檢查的現象中。一般而言，據信時鐘機制由負轉錄/翻譯反饋環（TTFL）組成，其具有相似的結構，但是在各種生物中包含不同的組分。但是，在其他物種中，包括模型植物擬南芥中的蟲草素的施用，也改變了時鐘相位。因此，RUVBL2可能是轉錄調控大復合體中僅有的少數保守成分之一，探索它的作用機制可望解析原初生物鐘最古老的進化來源問題。

2. 晝夜節律時鐘與睡眠的互作問題

一般人們普遍認為，打斷睡眠會影響大腦內的生物鐘運行。例如，人們經常抱怨說，哪怕只是輕微的睡眠干擾，他們的內在生物鐘也會受到干擾。實際上，根據臨床報告，在睡眠剝奪6小時后，一些激素的振蕩（例如生長激素和甲狀腺素T3/T4）會被抑制。我們開發出來了一套基于光纖技術應用的長時間實時檢測系統，可以用來監控活體哺乳動物的腦鐘，于是我們利用它來測量睡眠剝奪（sleep-deprived）和睡眠反彈（sleep-rebound）條件下的腦鐘運行。出乎意料的是，我們發現睡眠剝奪或其反彈期間視交叉上核（SCN）中晝夜節律生物鐘的振蕩幾乎沒有變化。對此現象的一種解釋是，可能還有其他一些大腦區域更容易受到睡眠剝奪的影響。因此，我們對了解這些區域可能位于何處，睡眠剝奪（和/或恢復）如何影響其本地鐘以及可能涉及哪些生物信號感興趣。這些研究可能有助于理解睡眠的本質基礎。

3. 晝夜節律的轉化醫學

我們長期以來一直在關注人類時間生物學。在最近一期的《晝夜節律生物鐘專輯》組稿中，我們專門配發了一篇社論，宣稱“生物鐘的轉化醫學時代已經來臨”（Go Human! Circadian Translational Medicine Has Come of Age）。在本實驗室的新階段，我們計劃與國內的一些醫院合作，更加專注于人類時鐘生物學。例如，我們最近從一項基于家庭譜系的人類遺傳研究中確定了一種雙突變型PER2，它會導致晝夜節律行為受到干擾。此外，據報道，老年人的時鐘較弱，而我們對哺乳動物的研究表明，帶有EPAS1突變體的藏族人的時鐘也可能會受干擾。此外，我們目前正在設計非侵入性方法來監測人類的時鐘動態和睡眠質量。

最后，我們由于近期發現了一組調節時鐘相位和振幅的化合物，證明了它們有治療潛力。我們現在的目標是與NIBS spin-off公司合作，以解決時差、輪班工作以及人類衰老的防治問題。

所有學術論文 All Publications:

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

節選發表文章 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”}

專利 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)

受邀報告 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