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張二荃博士

北京生命科學(xué)研究所資深研究員

E. Erquan Zhang, Ph.D.

Investigator, NIBS, Beijing，China

Phone：010-80726688-8605

Fax： 010-80727512

E-mail：zhangerquan@nibs.ac.cn

教育經(jīng)歷

Education

2000 – 2004	美國加州大學(xué)圣地亞哥分校分子病理專業(yè)博士
	Ph.D. in Molecular Pathology, University of California – San Diego, La Jolla, California, USA
1994 – 1997	復(fù)旦大學(xué)生物化學(xué)專業(yè)碩士
	M.S. in Biochemistry, Fudan University, Shanghai, China
1990 – 1994	華東師范大學(xué)環(huán)境科學(xué)專業(yè)學(xué)士
	B.S. in Environmental Science, East China NormalUniversity, Shanghai, China

工作經(jīng)歷

Professional Experience

2025 –	北京生命科學(xué)研究所資深研究員
	Investigator, National Institute of Biological Sciences, Beijing, China

2020 – 2025	北京生命科學(xué)研究所高級(jí)研究員
	Associate Investigator, National Institute of Biological Sciences, Beijing, China
2011 – 2020	北京生命科學(xué)研究所研究員
	Assistant Investigator, National Institute of Biological Sciences, Beijing, China
2006 – 2010	美國諾華制藥加州圣地亞哥研究院高級(jí)博士后研究員；兼美國加州大學(xué)圣地亞哥分校生物科學(xué)學(xué)院訪問學(xué)者
	Institute Fellow, Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Visiting Scholar, Division of Biological Sciences, University of California – San Diego, La Jolla, California, USA
2004 – 2006	美國加州斯科瑞普斯研究所博士后
	Postdoctoral Associate, The Scripps Research Institute, La Jolla, California, USA

研究概述

過去多年中我們一直在探索各種哺乳動(dòng)物的晝夜節(jié)律機(jī)制和功能。在已取得的一些重要發(fā)現(xiàn)的基礎(chǔ)上，我們實(shí)驗(yàn)室在NIBS的新階段可以更加專注于以下三個(gè)特定的科學(xué)目標(biāo)。

1. 晝夜節(jié)律時(shí)鐘的“A”類影響：腺苷、ATP與ATPase

我們前期的化學(xué)篩選找到了一類可能調(diào)節(jié)晝夜節(jié)律的腺苷類似物（包括蟲草素cordycepin），并證明了其生理代謝產(chǎn)物的靶標(biāo)是新型時(shí)鐘成分，即一種名為RUVBL2的AAA+ 型ATPase，其作用是負(fù)責(zé)該功能的巨型超復(fù)合物晝夜節(jié)律轉(zhuǎn)錄。有趣的是，我們觀察到了蟲草素（及其它腺苷類似物）對(duì)時(shí)鐘調(diào)節(jié)的跨物種甚至跨界的影響，這表明進(jìn)化上保守的機(jī)制可能隱藏在我們?cè)趯?shí)驗(yàn)室定期檢查的現(xiàn)象中。一般而言，據(jù)信時(shí)鐘機(jī)制由負(fù)轉(zhuǎn)錄/翻譯反饋環(huán)（TTFL）組成，其具有相似的結(jié)構(gòu)，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(shí)鐘相位。因此，RUVBL2可能是轉(zhuǎn)錄調(diào)控大復(fù)合體中僅有的少數(shù)保守成分之一，探索它的作用機(jī)制可望解析原初生物鐘最古老的進(jìn)化來源問題。

2. 晝夜節(jié)律時(shí)鐘與睡眠的互作問題

一般人們普遍認(rèn)為，打斷睡眠會(huì)影響大腦內(nèi)的生物鐘運(yùn)行。例如，人們經(jīng)常抱怨說，哪怕只是輕微的睡眠干擾，他們的內(nèi)在生物鐘也會(huì)受到干擾。實(shí)際上，根據(jù)臨床報(bào)告，在睡眠剝奪6小時(shí)后，一些激素的振蕩（例如生長(zhǎng)激素和甲狀腺素T3/T4）會(huì)被抑制。我們開發(fā)出來了一套基于光纖技術(shù)應(yīng)用的長(zhǎng)時(shí)間實(shí)時(shí)檢測(cè)系統(tǒng)，可以用來監(jiān)控活體哺乳動(dòng)物的腦鐘，于是我們利用它來測(cè)量睡眠剝奪（sleep-deprived）和睡眠反彈（sleep-rebound）條件下的腦鐘運(yùn)行。出乎意料的是，我們發(fā)現(xiàn)睡眠剝奪或其反彈期間視交叉上核（SCN）中晝夜節(jié)律生物鐘的振蕩幾乎沒有變化。對(duì)此現(xiàn)象的一種解釋是，可能還有其他一些大腦區(qū)域更容易受到睡眠剝奪的影響。因此，我們對(duì)了解這些區(qū)域可能位于何處，睡眠剝奪（和/或恢復(fù)）如何影響其本地鐘以及可能涉及哪些生物信號(hào)感興趣。這些研究可能有助于理解睡眠的本質(zhì)基礎(chǔ)。

3. 晝夜節(jié)律的轉(zhuǎn)化醫(yī)學(xué)

我們長(zhǎng)期以來一直在關(guān)注人類時(shí)間生物學(xué)。在最近一期的《晝夜節(jié)律生物鐘專輯》組稿中，我們專門配發(fā)了一篇社論，宣稱“生物鐘的轉(zhuǎn)化醫(yī)學(xué)時(shí)代已經(jīng)來臨”（Go Human! Circadian Translational Medicine Has Come of Age）。在本實(shí)驗(yàn)室的新階段，我們計(jì)劃與國內(nèi)的一些醫(yī)院合作，更加專注于人類時(shí)鐘生物學(xué)。例如，我們最近從一項(xiàng)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(huì)導(dǎo)致晝夜節(jié)律行為受到干擾。此外，據(jù)報(bào)道，老年人的時(shí)鐘較弱，而我們對(duì)哺乳動(dòng)物的研究表明，帶有EPAS1突變體的藏族人的時(shí)鐘也可能會(huì)受干擾。此外，我們目前正在設(shè)計(jì)非侵入性方法來監(jiān)測(cè)人類的時(shí)鐘動(dòng)態(tài)和睡眠質(zhì)量。

最后，我們由于近期發(fā)現(xiàn)了一組調(diào)節(jié)時(shí)鐘相位和振幅的化合物，證明了它們有治療潛力。我們現(xiàn)在的目標(biāo)是與NIBS spin-off公司合作，以解決時(shí)差、輪班工作以及人類衰老的防治問題。

所有學(xué)術(shù)論文All Publications:

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

節(jié)選發(fā)表文章Selected Publications:

1. 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)

2. 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. Cell Reports, 43:114727 (2024)

3. 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”; Featured by Cell “Best papers of 2024”}

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

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 {Highlighted by Nature Reviews Gastroenterology & Hepatology: “Stopped clock promotes fibrosis in chronic pancreatitis”}

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) Cell 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 {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)}

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 {Featured by Editor in the issue: “The skinny on FTO”}

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 {Highlighted by Faculty of 1000 (Very Good)}

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) Cell Metabolism 25: 73-85 {Cover story of the issue; Featured by Science Signaling, “Daily oxygen rhythms”}

專利 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 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(bào)告 Invited Talks in Conferences:

1. 19th ITMAT Annual International Symposium, University of Pennsylvania, Philadelphia, USA, October 2024

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

3. 7th Asian Forum on Chronobiology, Sapporo, JAPAN, August 2024 (Keynote Speaker)

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

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

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

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

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

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

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

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

12. 5th World Congress of Chronobiology, Suzhou, CHINA, April 2019 (Co-organizer)

13. 1st Beijing International Symposium on the Circadian Clock and Sleep Research, Beijing, CHINA, April 2019 (Co-organizer)

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

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

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

17. 2nd Asian Forum on Chronobiology, Hohhot, Inner Mongolia, CHINA, June 2017 (Co-organizer)

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

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科學(xué)研究

張二荃博士

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