张二荃博士 - 科學研究

张二荃博士

仁信彩票研究員

E. Erquan Zhang, Ph.D. Assistant Investigator, NIBS, Beijing，China

Phone：010-80726688-8605

Fax： 010-80727512

E-mail：zhangerquan@nibs.ac.cn

教育經曆

Education

2000 – 2004	美國加州大學聖地亞哥分校分子病理專業博士
	Ph.D. in Molecular Pathology, University of California – San Diego, La Jolla, California, USA
1994 – 1997	複旦大學生物化學專業硕士
	M.S. in Biochemistry, Fudan University, Shanghai, China
1990 – 1994	華東師範大學环境科學專業學士
	B.S. in Environmental Science, East China NormalUniversity, Shanghai, China

工作經曆

Professional Experience

2011 –	北京生命科學研究所研究員
	Assistant Investigator, National Institute of Biological Sciences, Beijing, China
2006 – 2010	美國诺华制藥加州聖地亞哥研究院高級博士後研究員；兼美國加州大學聖地亞哥分校生物科學學院访问學者
	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後
	Postdoctoral Associate, The Scripps Research Institute, La Jolla, California, USA

研究概述

生物鍾對人類行爲與生理有廣泛的調節作用。我們對生物鍾研究領域各個方面都感興趣，主要想回答三大問題：什麽是生物鍾？生物鍾如何進行調控？研究生物鍾有何关键意義？目前我們對以下幾個子課題特別感興趣：

1.	對于哺乳動物的生物鍾而言，一個簡單的模型就是轉錄因子形成的延遲負反饋系統：轉錄正因子CLOCK和BMAL1結合，激活轉錄負因子PERIOD（包括PER1, PER2, PER3；簡稱PER）和CRYPTOCHROME（CRY1, CRY2；簡稱CRY）。PER與CRY表達積累到一定程度會反過來抑制CLOCK-BMAL1的活性，從而導致PER-CRY表達降低，形成每循環約24小時的負反饋環路。早期的小鼠行爲篩選以及最近的全基因siRNA筛选都显示有更多的生物钟基因存在。我们准备运用系统生物學结合小鼠遗传學方法研究新的生物钟基因及其调控转录的分子机理，更深入理解生物钟振荡器的相位，振幅，及周期。
2.	視交叉上核（SCN）是負責生物鍾調控的主要器官，位于下丘腦前端。前期研究表明，SCN中存在一种特异性的分子机制暂时不明的耦合机理，促使其内的生物钟异常强劲。我们准备运用合成生物學方法改造成纤维细胞，外加某种假设的耦合机理，使其变成SCN神經細胞。如獲得成功，我們就不僅解釋了耦合的分子機理，也會提供足夠的材料作生化分析，用以更深層次的解釋何以SCN區別于其它組織而作爲生物鍾調控的中心。
3.	生物钟失调会导致代谢紊乱。为了充分发挥本研究員以前做高通量筛选（HTS）的特長已及應用NIBS擁有的最先進的HTS设备，我们会用此技术开创几个探索性课题，用以了解生物钟对酒精代谢和脂肪肝形成的影响。从这些细胞筛选方法得到的假说，我们会进一步运用小鼠遗传學等体内方法来加以验证。

Research Description

Circadian clock regulates human behavior and physiology. We are interested in understanding all aspects of circadian rhythms: What is the clock? How does the clock run? Why is the clock relevant? In particular, we focus on several projects in dissecting the clock mechanism and highlighting its biological/biomedical significance:

1.	In a simplified model, transcriptional activators CLOCK and BMAL1 stimulate PERIOD (PER1, PER2 and PER3) and CRYPTOCHROME (CRY1, CRY2) repressors that feed back on CLOCK-BMAL1 activity. Both mouse behavioral and genome-wide RNAi screens suggest that there are more clock genes to be identified. Using systems biology and mouse genetics approaches, we aim to understand the detailed molecular basis of transcriptional regulations on clock phase, amplitude, and period-length.
2.	Suprachiasmatic nucleus (SCN) is the clock master organ, located in the anterior hypothalamus. Previous studies indicated that the coupling mechanism distinguishes the SCN from other peripheral tissues in controlling the robustness of the clock. Using synthetic biology tools, we aim to reconstitute fibroblast cells, an exemplary model for peripheral clocks, into SCN neurons by transplanting the coupling system. A successful recapitulation of SCN properties by manipulating fibroblasts will not only offer mechanistic insights for the coupling, but also provide sufficient materials for biochemical characterization, allowing us to understand the uniqueness of clock master regulation.
3.	Metabolic disorders are linked to malfunctions of the circadian clock. To fully benefit from the PI’s expertise on high-throughput screening (HTS) and the “state-of-the-art” HTS facility at NIBS, we plan to conduct a few pilot/exploratory projects to understand the clock’s impacts on alcohol metabolism and fatty-liver development. Hypotheses generated from these cell-based screens will be further tested in vivo.

發表文章节选

Selected Publications:

1. 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); Detailed protocol can be viewed in a video publication of JOVE 56765}

2. 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” (Editors' Choice)}

3. Zhang, E.E.* and Kay, S.A.? Clocks Not Winding Down: Unraveling Circadian Networks. (2010) Nature Reviews Molecular Cell Biology 11: 764-776 {Invited Review, 10-year Anniversary Series}

4. Zhang, E.E.*, Liu, Y.*, Dentin, R., Pongsawakul, P.Y., Liu, A.C., Hirota, T., Nusinow, D.A., Sun, X., Landais, S., Kodama, Y., Brenner, D., Montminy, M.? and Kay, S.A.? Cryptochrome Mediates Circadian Regulation of cAMP Signaling and Hepatic Gluconeogenesis. (2010) Nature Medicine 16: 1152-1156 {Featured by Nature Medicine, “High glucose, no cry” (News and Views); Highlighted by Faculty of 1000 (Very Good)}

5. Zhang, E.E.*, Liu, A.C.*, Hirota, T.*, Miraglia, L.J., Welch, G., Pongsawakul, P.Y., Liu, X., Atwood, A., Huss, J.W.III., Janes, J., Su, A.I., Hogenesch, J.B.?, and Kay,S.A.? A Genome-wide siRNA Screen for Modifiers of the Circadian Clock in Human Cells. (2009) Cell 139: 199-210 {Highlighted by Faculty of 1000 (Exceptional)}

6. Zhang, E.E.*, Chapeau, E., Hagihara, K. and Feng, G-S.? Neuronal Shp2 Tyrosine Phosphatase Controls Energy Balance and Metabolism. (2004) Proceedings of the National Academy of Sciences U.S.A. 110: 16064-16069

仁信彩票

科學研究

張二荃博士