张宏博士 - 科学研究 - 北京生命科学研究所

张宏博士

北京生命科学研究所高级研究员

Hong Zhang, Ph.D.

Associate Investigator, NIBS, Beijing, China

教育经历

Education

1991	安徽大学生物化学系学士
	B.S.Biochemistry, July 1991, Anhui University
2001	美国纽约 Albert Einstein College of Medicine 分子遗传学博士
	Ph.D Molecular Genetics, January 2001, Albert Einstein College of Medicine. USA

工作经历

Professional Experience:

2009-2012	北京生命科学研究所高级研究员
	Associate Investigator at National Institute of Biological Sciences,Beijing, China
2004-2009	北京生命科学研究所研究员
	Assistant Investigator at National Institute of Biological Sciences,Beijing, China
2001- 2004	哈佛大学医学院、马萨诸塞总医院癌症中心研究员
	Massachusetts General Hospital Cancer Center, Harvard MedicalSchool, Research Fellow

研究概述

我们实验室的兴趣主要集中在研究多细胞生物中自噬作用的机理和调控机制。自噬作用是细胞内主要的代谢方式，它是通过形成一种叫做自噬小体的双膜结构来包裹细胞质和一些受损的细胞器并将它们运送到溶酶体中降解。在哺乳动物中，自噬作用在许多生理过程中发挥着极其重要的作用，包括对营养胁迫的应激性，对抗外来病原入侵以及对一些有毒性倾向的蛋白的降解。自噬作用的紊乱会引起许多病理反应，包括神经退行性疾病，肝功能异常，心肌梗塞，肿瘤发生等严重疾病。在多细胞生物里，自噬小体的诱导和形成的机制在很大程度上仍然是未知的。而且在动物发育过程中，自噬作用如何选择性识别并降解特异性底物也是存在许多争议。秀丽线虫(C. elegans)拥有一成不变的细胞谱系、丰富的实验手段，例如利用遗传筛选将不同基因归类到一条通路之中等等，这些丰富的发育生物学的背景使得秀丽线虫成为研究自噬作用过程以及蛋白质聚集体的选择性降解机制的良好模型。

我们实验室的前期工作已经在选择性降解方面取得重大突破，发现在线虫胚胎发育过程中生殖细胞的P颗粒能够被自体吞噬选择性降解，克隆了SEPA-1这个介导P颗粒被自噬系统选择性降解的关键因子，此外我们还克隆了线虫中的ATG13的功能同源基因epg-1，发现了多细胞生物特异的参与自噬作用的四个基因epg-2，epg-3，epg-4和epg-5及它们的作用机理。

实验室以后的工作主要集中在：

1. 利用线虫遗传学的优势继续大规模筛选更多的参与自体吞噬的相关基因。

2. 研究P颗粒等自噬降解的底物如何被选择性降解的机理。

3. 研究自体吞噬的活性在生物体发育过程中的变化关系。

4. 研究自体吞噬对衰老的影响。

5. 揭示自体吞噬在神经细胞保护方面的功能。

Research Description

Autophagy, an evolutionarily conserved intracellular catabolic process, involves formation of a double membrane structure, called the autophagosome, which engulfs portions of the cytosol and delivers them to lysosomes for degradation. In higher eukaryotes, autophagy is important for diverse processes, such as adaptation to starvation and stress, removal of aggregate-prone proteins and elimination of pathogens. Deregulated autophagy has been linked to pathologic conditions such as neurodegeneration, cardiomyopathy and tumor progression. Studies of autophagy in higher eukaryotes are greatly facilitated by the functional conservation of yeast Atg proteins. However, autophagy in higher eukaryotes involves much more complex membrane dynamics. Thus, it is conceivable that the higher eukaryote autophagy pathway might require more elaborate molecular machinery, including factors that are absent in yeast. So far, very little is known about higher eukaryote-specific autophagy components.

We demonstrated that autophagy is required for degradation of several aggregate prone proteins during C. elegans embryogenesis, including germline P granule components in somatic cells. We further performed genetic screens to isolate mutants with defective degradation of autophagy substrates and identified four previously uncharacterized, higher eukaryote-specific autophagy genes, epg-2, -3, -4 and -5, which define discrete genetic steps in the autophagy pathway. Our study establishes C. elegans as a multicellular genetic model to delineate the autophagy pathway. Our findings using this system provide a genetic framework for further study of basal and selective autophagic degradation of protein aggregates in mammalian cells.

Publications:

1. Huang, X.X., Zhang, H. and Zhang, H. (2011) The zinc finger protein SEA-2 regulates larval developmental timing and adult life span in C. elegans. Development (in press).

2. Yang, P.G. and Zhang, H. (2011) The coiled-coil domain protein EPG-8 plays an essential role in the autophagy pathway in C. elegans. Autophagy 7, 159-165.

3. Ren, H.Y. and Zhang, H. (2010) Wnt signaling controls temporal identities of seam cells in Caenorhabditis elegans. Developmental Biology 345, 144-155.

4. Tian, Y., Li Z. P., Hu, W. Q., Ren H. Y., Tian, E., Zhao, Y., Lu, Q., Huang, X. X., Yang, P. G., Li, X., Wang, X. C., Kovács, A. L., Yu, L., and Zhang, H. (2010) C. elegans screen identifies autophagy genes specific to multi-cellular organisms. Cell 141, 1042-55.

5. Kovács, A.L, and Zhang, H. (2010) Role of autophagy in Caenorhabditis elegans. FEBS Lett. 584, 1335-41.

6. Huang, X.X., Tian, E, Xu, Y.H., and Zhang, H. (2009) The C. elegans engrailed homologceh-16 regulates the self-renewal expansion division of stem cell-like seam cells.Developmental Biology 333, 337-347.

7. Xia, D., Huang, X.X., and Zhang, H. (2009) The temporally regulated transcription factor sel-7 controls the developmental timing in C. elegans. Developmental Biology332, 246-257.

8. Tian, E, Wang, F.X., Han, J.H., and Zhang, H. (2009) epg-1 functions in the autophagy pathway and may encode a highly divergent Atg13 homolog in C. elegans.Autophagy 5, 608-615.

9. Zhao, Y., Tian, E, and Zhang, H. (2009) Selective autophagic degradation of maternally loaded germline P granule components in somatic cells during C. elegansembryogenesis. Autophagy 5, 717-719.

10. Zhang, Y.X., Yan, L.B., Zhou, Z., Yang, P.G., Tian E, Zhang, K., Zhao, Y., Li, Z.P., Song, B., Han, J.H., Miao, L., and Zhang, H. (2009) SEPA-1 mediates the specific recognition and degradation of P granule components by autophagy in C. elegans.Cell 136, 308-321.

11. Cai, Q.C., Sun, Y.Y., Huang, X.X., Guo, C., Zhang, Y.X., Chen, Y.Y., and Zhang, H.(2008) The C. elegans PcG-like gene sop-2 coordinately regulates the temporal, spatial, and sexual specificities of cell fates. Genetics 178, 1445-1456.

12. Deng, H., Xia, D., Fang, B., and Zhang, H. (2007) The Flightless I homolog, fli-1,regulates anterior-posterior polarity, asymmetric cell division and ovulation during C. elegans development. Genetics 177, 847-860.

13. Xia, D., Zhang, Y.X., Huang, X.X., Sun, Y.Y., and Zhang, H. (2007) The C. elegansbCBF homolog, BRO-1, regulates the proliferation, differentiation and specification of the stem cell-like seam cell lineages. Developmental Biology 309, 259-272.

14. Deng, H., Sun, Y.Y, Zhang, Y.X., Luo, X., Hou, W.R., Tian, E, Han, J.H., and Zhang, H.(2007) The C. elegans NF-Y complex functions as PcG proteins in Hox gene repression. Developmental Biology 308, 583-592.

15. Yang, Y., Sun, Y.Y., Luo, X., Zhang, Y.X., Chen, Y.Y., Tian, E, Lints, R., and Zhang, H.(2007) Polycomb-like genes are necessary for specification of dopaminergic and serotonergic neurons in Caenorhabditis elegans. PNAS 104, 852-857.

16. Zhang, T., Sun, Y., Tian, E, Deng, H., Zhang, Y., Luo, X., Cai, Q., Wang, H., Chai, J., and Zhang, H. (2006) RNA-binding proteins SOP-2 and SOR-1 form a novel PcG-like complex in C. elegans. Development 133, 1023-1033.

17. Sun, Y., and Zhang, H. (2005) A Unified Mode of Epigenetic Gene Silencing: RNA Meets Polycomb Group Proteins. RNA biology 2, 8-10.

18. Zhang, H., Christoforou, A., Aravind, L., Emmons, S.W., van den Heuvel, S., and Haber, D.A. (2004) The C. elegans Polycomb gene sop-2 encodes an RNA binding protein. Molecular Cell 14, 841-847.

19. Zhang, H., Smolen, G., Palmer, R., Christoforou, A., van den Heuvel, S., and Haber, D.A. (2004) SUMO modification is required for in vivo Hox gene regulation by the C. elegans Polycomb group protein SOP-2. Nature Genetics 36, 507-511.

20. Zhang, H., Palmer, R., Gao, X., Kreidberg, J., Gerald, W., Hsiao, L., Jensen, R.V., Gullans, S.R., and Haber, D.A. (2003) Transcriptional Activation of Placental Growth Factor by the Forkhead/Winged Helix Transcription Factor FoxD1. Current Biology 13, 1625-1629.

21. Zhang, H., Azevedo, R.B., Lints, R., Doyle, C., Teng, Y., Haber, D., and Emmons, S.W. (2003) Global regulation of Hox gene expression in C. elegans by a SAM domain protein. Developmental Cell 4, 903-915.

22. Zhang H., and Emmons S.W. (2002) C. elegans unc-37/groucho interacts genetically with components of the transcriptional mediator complex. Genetics 160, 799-803.

23. Zhang, H., and Emmons S.W. (2001) The novel C. elegans gene sop-3 modulates the Wnt signaling to regulate the expression and function of Hox genes. Development128, 767-777.

24. Zhang, H., and Emmons, S.W. (2000) A C. elegans mediator protein confers regulatory stringency on lineage-specific expression of a transcription factor gene.Genes & Development 14, 2161-2172.

Invited review:

Tian, Y., Ren, H.Y., Zhao, Y., Lu, Q., Huang, X.X., Yang, P.G., and Zhang, H. (2010)Four metazoan autophagy genes regulate cargo recognition, autophagosome formation and autolysosomal degradation. Autophagy 6, 984-985.

Kovács, A.L. and Zhang, H. (2010) Role of autophagy in Caenorhabditis elegans. FEBS letters 584, 1335-1341.

Sun, Y.Y. and Zhang, H. (2005) A Unified Mode of Epigenetic Gene Silencing: RNA Meets Polycomb Group Proteins. RNA biology 2, 8-10.