佟超

佟超博士，浙江大学生命科学研究院教授、研究员、博士生导师。办公地点：医学院科研楼A401；电话：0571-88981582；传真：0571-88981582；Email: ctong@zju.edu.cn；实验室网站：http://lsi.zju.edu.cn/yjdw_detail.aspx?ID=16。

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1995-1999：南开大学 生化及分子生物学系 学士
1999-2002：中国科学院动物研究所 生殖生物学 硕士

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• 2000：中国科学院董事东方奖学金
• 2002：中国科学院院长奖学金优秀奖
• 2007：Developmental biology training grant
• 2008：“Brain disorders and Development” training grant
• 2004-至今：member of Genetics society of America

研究组致力于研究神经系统发育及神经退行性疾病的分子机制。主要感兴趣的问题是神经细胞轴突如何找到其靶细胞并与之建立精确突触连接，以及细胞自噬通路如何维持神经细胞完整性防止神经退行性疾病的发生。通过果蝇遗传筛选的方法寻找参与神经轴突定位及神经细胞完整性维持的新基因，阐明其作用的分子机理，并最终在高等动物中检验此作用机制的保守性，从而为临床实践提供理论依据。

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一、神经元轴突定位

在大脑发育过程中，10亿个神经元整合多种信号相互连接形成约1兆个神经突触。神经元轴突寻找其靶细胞并与之建立精确突触连接对于神经系统的发育和神经回路的建立至关重要。不正常的轴突定向及突触连接可以导致多种神经系统先天疾病，例如智障，自闭症，以及神经退行性疾病。果蝇的视觉神经系统因其结构的模块性，进化上的保守性，以及实验上的可操作性为解析神经元轴突定向及突触连接建立的分子机理提供了极好的模型。通过大规模遗传筛选发现一个进化上保守的新基因rich调节感光神经细胞R7的轴突定向。Rich蛋白与Rab6结合并正向调节Rab6的活性，进而影响细胞表面粘联蛋白N-Cadherin的分布，造成R7轴突定位异常。将进一步研究N-Cadherin在细胞中的运输方式，继续研究Rich如何调节Rab6活性，并进而研究Rich哺乳动物同源基因的功能。

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二、细胞自噬与神经退行性疾病

随着人类寿命的增长，神经退行性疾病的发生日益普遍。神经元细胞寿命很长，又不能通过细胞分裂稀释细胞中异常的蛋白和损坏的细胞器。识别并清除这些废物，防止他们的堆积造成的细胞毒性对神经细胞来讲十分重要。细胞自噬功能异常在神经退行性疾病中相当普遍。在小鼠和果蝇中敲除细胞自噬相关基因，均可诱导神经退行性疾病类似症状。调节细胞自噬功能可以减缓多种神经退行性疾病症状。通过大规模遗传筛选，发现多个果蝇突变株具有细胞自噬障碍。其中一些基因的突变在人类中导致神经退行性疾病，但其功能从未与细胞自噬连系起来。此外，还发现同是编码线粒体蛋白的基因，有些基因的突变会促进细胞自噬，而另外一些的突变却抑制细胞自噬。在这些已筛出的基因中还有参与细胞中重要信号通路的分子，参与细胞内膜泡运输的分子，以及未知功能的新基因。 ADSFAEQWER353423413434

Our major research interest is to dissect the molecular mechanisms that underline neuronal development and neural degeneration diseases. Particularly, we are interested in how neurons find their targets and how autophagy/lysosomal pathway contribute to neuronal health maintenance. Our goal is to identify novel players and to define molecular pathways in neural development and maintenance by using Drosophila as a model system. Eventually, we want to apply these discoveries to the higher organisms. We hope our study can provide clues for clinical treatments of cognitive diseases and neural degeneration. Meanwhile, we hope our study could expand our understanding of the general autophagy/lysosomal pathway which is also involved in multiple important physiological and pathological processes such as immune-response and cancer in addition to neural health maintenance.

Neuronal specificity

During development, more than 100 billion neurons in our brain form trillions synaptic connections. To achieve this, neurons integrate numerous signals that allow them to decide when to extend their growth cones, to follow a specific route, to determine when to fasciculate or defasciculate, and when to stop and form synaptic connections. Improper synapse formation may lead to cognitive diseases and mental retardation such as autism spectrum disorders. The Drosophila visual system is an excellent model to untangle this type of question. By using forward genetic screen, we identified mutations in rich, a novel gene that is evolutionarily conserved from worms to human. We found that rich is required for synaptic specificity in Drosophila eyes and olfactory neurons and regulate Rab6 activity. Our data define a novel role for Rich and Rab6 in regulating synaptic specificity by regulating trafficking of CadN but not other proteins implicated in this process. In the future, we will further investigate how CadN is trafficked inside cells. We will also like to further understand the molecular nature of Rich and elucidate how Rich regulates Rab6. In addition, we also like to study the functions of the mammalian homolog.

Neurodegeneration and autophagy/lysosomal pathway

At adulthood, neurons have to maintain cell integrity in response to genetic and environmental insults to sustain nerve system function and prevent degeneration. With increase of human life-span, neural-degeneration emerged as rather common diseases that greatly affect people's life quality. Drosophila has proved to be an excellent model to study neurodegeneration. As long-lived post-mitotic cells, neurons cannot dilute the altered proteins and damaged organelles by cell division. Therefore, to identify and reduce these malfunction structures before they buildup and cause neurotoxicity is particularly important to neurons. Autophagy/lysosomal pathway plays important role in this clearance process, evidenced by autophagic malfunction in many human neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). Genetically deleted autophagy related genes (Atgs) in mice and flies results neural degeneration. In contrast, modulating autophagy has beneficial effects in many neurodegenerative disorders. We carried out a forward genetic screen to identify novel players involved in autophagy/lysosomal pathway. So far, we have identified more than 60 mutant complementation groups with autophagy defects. Among these mutants, some genes have already been implied involved in neurodegeneration diseases in human, but their functions have never been linked to autophagy pathway. We also find genes encoding mitochondrial proteins play diverse roles in autophagy pathway, some mutants block autophagy while the others enhance autophagy. In addition, we also found proteins involved in signal transduction, membrane trafficking, as well as proteins with unknown function.

1. Tong, C., Ohyama, T., Tie, A., Rajan, A., Haueter, C., Bellen, HJ. Rich regulates target specificity of photoreceptor cells and N-Cadherin trafficking in the Drosophila visual system via Rab6. Neuron Accepted. ADFASDFAF23RQ23R

2. Jia, H., Liu, Y., Xia, R., Tong, C., Yue, T., Jiang, J., Jia, J. (2010). Casein kinase 2 promotes hedgehog signaling by regulating both smoothened and cubitus interruptus. J Biol Chem. 285(48):37218-26. ADFASDFAF23RQ23R

3. Chen, Y., Li, S., Tong, C., Zhao, Y., Wang, B., Liu, Y., Jia, J., Jiang, J. (2010). G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila. Genes Dev. 24(18):2054-67. ADFASDFAF23RQ23R

4. Bellen, HJ., Tong, C., Tsuda, H. (2010). 100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future. Nat Rev Neurosci. 11(7), 514-522.

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5. Tsuda, H., Han, SM., Yang, Y., Tong, C., Lin, YQ., Mohan, K., Haueter, C., Zoghbi, A., Harati, Y., Kwan, J., Miller, MA., Bellen HJ. (2008). The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell. 133(6), 963-77. ADFASDFAF23RQ23R

6. Zhao, Y., Tong, C., Jiang, J. (2007). Transducing the Hedgehog signal across the plasma membrane. Fly.1(6), 333-6. ADSFAEQWER353423413434

7. Tong, C., Jiang, J. (2007). Using immunoprecipitation to study protein-protein interactions in the hedgehog signaling pathway. Methods Mol Biol. 397, 215-30.

8. Zhao, Y., Tong, C., Jiang, J. (2007). Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450, 252-8. (共同第一作者) ADFASDFAF23RQ23R

9. Jia, J., Zhang, L., Zhang, Q., Tong, C., Wang, B., Hou, F., Amanai, K., and Jiang, J. (2005). Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/beta-TRCP mediated proteolytic processing. Developmental Cell 9, 819-830.

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10. Zhang, W., Zhao, Y., Tong, C., Wang, G., Wang, B., Jia, J., and Jiang, J. (2005). Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Developmental Cell 8, 267-278. ADFASDFAF23RQ23R

11. Jia, J., Tong, C., Wang, B., Luo, L., and Jiang, J. (2004). Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432, 1045-1050. (共同第一作者) ADSFAEQWER353423413434

12. Jia, J., Tong, C., and Jiang, J. (2003). Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail. Genes and Development 17, 2709-2720. ADFASDFAF23RQ23R

13. Moskalenko, S., Tong, C., Rosse, C., Mirey, G., Formstecher, E., Daviet, L., Camonis, J., and White, M. A. (2003). Ral GTPases regulate exocyst assembly through dual subunit interactions. The Journal of biological chemistry 278, 51743-51748. ADFASDFAF23RQ23R

14. Tong, C., Fan, H. Y., Chen D, Y., Song, X. F., Schatten, H., and Sun, Q. Y. (2003). Effects of MEK inhibitor U0126 on meiotic progression in mouse oocytes: microtubule organization, asymmetric division and metaphase II arrest. Cell Research 13, 375-383. ADSFAEQWER353423413434

15. Fan, H. Y., Tong, C., Teng, C. B., Lian, L., Li, S. W., Yang, Z. M., Chen, D. Y., Schatten, H., and Sun, Q.Y. (2003). Characterization of Polo-like kinase-1 in rat oocytes and early embryos implies its functional roles in the regulation of meiotic maturation, fertilization, and cleavage. Molecular Reproduction and Development 65, 318-329.

16. Fan, H. Y., Tong, C., Lian, L., Li, S. W., Gao, W. X., Cheng, Y., Chen, D. Y., Schatten, H., and Sun, Q. Y. (2003). Characterization of ribosomal S6 protein kinase p90rsk during meiotic maturation and fertilization in pig oocytes: mitogen-activated protein kinase-associated activation and localization. Biology of Reproduction 68, 968-977. ADSFAEQWER353423413434

17. Cheng, Y., Fan, H. Y., Wen, D. C., Tong, C., Zhu, Z. Y., Lei, L., Sun, Q. Y., and Chen, D. Y. (2003). Asynchronous cytoplast and karyoplast transplantation reveals that the cytoplasm determines the developmental fate of the nucleus in mouse oocytes. Molecular Reproduction and Development 65, 278-282. ADFASDFAF23RQ23R

18. Yao, L. J., Fan, H. Y., Tong, C., Chen, D. Y., Schatten, H., and Sun, Q. Y. (2003). Polo-like kinase-1 in porcine oocyte meiotic maturation, fertilization and early embryonic mitosis. Cellular and molecular biology (Noisy-le-Grand, France) 49, 399-405. ADFASDFAF23RQ23R

19. Fan, H. Y., Li, M. Y., Tong, C., Chen, D. Y., Xia, G. L., Song, X. F., Schatten, H., and Sun, Q. Y. (2002). Inhibitory effects of cAMP and protein kinase C on meiotic maturation and MAP kinase phosphorylation in porcine oocytes. Molecular Reproduction and Development 63, 480-487. ADSFAEQWER353423413434

20. Fan, H. Y., Tong, C., Li, M. Y., Lian, L., Chen, D. Y., Schatten, H., and Sun, Q. Y. (2002). Translocation of the classic protein kinase C isoforms in porcine oocytes: implications of protein kinase C involvement in the regulation of nuclear activity and cortical granule exocytosis. Experimental Cell Research 277, 183-191. ADFASDFAF23RQ23R

21. Tong, C., Fan, H. Y., Lian, L., Li, S. W., Chen, D. Y., Schatten, H., and Sun, Q. Y. (2002). Polo-like kinase-1 is a pivotal regulator of microtubule assembly during mouse oocyte meiotic maturation, fertilization, and early embryonic mitosis. Biology of Reproduction 67, 546-554.

• Tong C, Ohyama T, Tie A, et al. Rich regulates target specificity of photoreceptor cells and N-Cadherin trafficking in the Drosophila visual system via Rab6. Neuron, 2011.
• Jia J, Tong C, Wang B, et al. Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature, 2004, 432: 1045-1050. (Co-first author)
• Bellen HJ, Tong C, Tsuda H. 100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future. Nat Rev Neurosci, 2010, 11(7): 514-522.
• Zhang W, Zhao Y, Tong C, et al. Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Developmental Cell, 2005, 8: 267-278.
• Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell, 2011, 147(4): 728-741.
• Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature, 2006, 443(7113): 780-786.
• 李英, 张洪. 果蝇在神经系统疾病研究中的应用. 生命科学, 2012, 24(5): 456-462.
• 王慧, 陈亮. 细胞自噬与神经退行性疾病的研究进展. 中国细胞生物学学报, 2018, 40(9): 1548-1555.