陈畅的主要研究方向 陈畅的介绍
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细胞的氧化还原调控失衡是导致亚健康、衰老、神经退行性疾病、炎症、肿瘤、糖尿病等的重要因素，因此，细胞氧化还原调控的分子机理研究具有重要理论和实际意义。近年研究发现：机体在应激条件下产生的一氧化氮等活性氮及活性氧小分子通过对蛋白质中氧化还原敏感的半胱氨酸巯基进行修饰，影响蛋白的结构、活性、定位、组装和降解，从而调控蛋白的功能和细胞信号传导，最终在生理和病理过程中发挥作用。这种修饰称为氧化还原依赖的蛋白翻译后修饰（Redox based post-translational modification of protein），包括：亚硝基化修饰(-SNO)、不同程度的氧化修饰（-S-S-; -S-OH; -SO3）、谷胱甘肽化修饰(-SSG)等，与磷酸化修饰一样，是两种进化上高度保守的蛋白翻译后修饰之一。我们致力于揭示生命活动中这些小分子和大分子的对白，揭示氧化还原依赖的蛋白质巯基翻译后修饰在细胞命运和疾病发生中的作用。重点研究一氧化氮生物活性及其对蛋白巯基的亚硝基化修饰在细胞信号转导中的作用。主要有以下三个方面。
1、蛋白质巯基修饰的功能和方法研究。
2、氧化应激/氮应激（oxidative stress/nitrosative stress）在疾病发生发展中的作用机理以及天然产物/中医药的调控和应用
3、肌醇磷脂4位激酶phosphatidylinositol 4-kinase type IIα (PI4KIIα)和一氧化氮代谢调控蛋白S-nitrosoglutathione reductase (GSNOR)的功能与分子机制研究。
主要成果：
? 揭示了亚硝基化修饰在调控蛋白核质转运中的作用，发现一氧化氮通过亚硝基化修饰调控核输出受体CRM1的功能，扩展了对核输出调控机制和一氧化氮生物学功能的认识。揭示了亚硝基化－泛素化－SUMO化三种蛋白质翻译后修饰的相互调控，本工作提示：调控其它蛋白质翻译后修饰可能是巯基亚硝基化修饰发挥作用的重要途径。
? 揭示了NO代谢调控对学习记忆的调控作用，率先提出NO生物活性受合成和代谢双调控的观点，部分揭示了NO代谢酶GSNOR在神经系统的生理意义。
? 发展定量高通量亚硝基化检测方法解决了内源亚硝基化检测难题；发现和排除了亚硝基化检测中的假阳性信号，引起本领域的广泛关注；尤其是我们建立了不可逆亲和素标记方法（IBP）, 是目前唯一能排除分子间二硫键干扰及-SSH巯基修饰的特异亚硝基化检测方法。
? 发现新的肿瘤生长调控蛋白Phosphatidylinositol 4-kinase type IIα，PI4KIIα. 该蛋白α亚型特异地调控HER-2/PI3K，ERK1/2 信号通路，调控HIF-1α蛋白的合成，影响了HIF-1下游促血管生成因子VEGF，iNOS等蛋白的表达，影响内皮细胞的成管及迁移能力进而影响血管新生，最终调控肿瘤的生长目前我们已构建PI4KIIα转基因鼠，正在进行PI4KIIα在肿瘤细胞转移方面的机理研究。
Biography & Introduction
Chang CHEN,PhD, Professor of Institute of Biophysics, ChineseAcademy of Sciences
1996, Ph.D. of Peking University
1998, associate professor of Institute of Biophysics, CAS;
1998-2000, visiting scientist in Institute of Food Research, UK; 2000- PI, Institute of Biophysics (2004, full professor), CAS.
Professional activities:
? Vice-president of the Society of Free Radical Biology and Medicine, China.
? Associated editor of the journal “Acta Biophysica Sinica” (the offical journal of the Biophysics Society of China).
? Editorial board member of “The Open Nitric Oxide Journal”.
? Editorial board member of “Progress in Biochemistry and Biophysics”.
Research interests:
Bioactivity of nitric oxide and redox-based protein thiol modification; Natural product development;Functional study of phosphatidylinositol 4-kinase type IIα (PI4KIIα) andS-nitrosoglutathione reductase (GSNOR) in transgenic mice.
NO, as a putative messenger, is implicated in physiological and pathological processes. Apart from the well-known cGMP-dependent signaling pathway of NO, there is also a cGMP-independent pathway that involves S- nitrosylation. S- nitrosylation is a ubiquitous redox-related modification of cysteine thiols by nitric oxide, which transduces the bioactivity of NO. The mechanism and the cellular effects of this redox-based post-translational modification of proteins are not well understood. Our approach to understanding this process involves three aspects:
1) Investigation of the effects of NO on the properties of proteins, such as folding kinetics, stability, enzyme activity and protein-protein interactions, complex assembling. This part of the work provides a basis for the study of the cellular effects.
2) We are interested in investigating how SNO affects intracellular events, such as protein localization, protein-protein interactions, and how NO and SNO affect the apoptosis and differentiation cascade. We are also screening natural products for activity as anti-oxidative/nitrosative stress agents.
3) Investigation of the effects of NO and SNO at the level of the whole organism, such as in memory, diseases (diabetes, cancer, neurodegenerative diseases).
As the chief scientist, Prof. Chen has been awarded several research grants, including from the National Basic Research Program of China (or 973 Program), the National High Technology Research and Development Program (863 Program), and the National Natural Science Foundation of China (NSFC), and the Yong scientist group project of Chinese Academy of Sciences, and the Chinese Academy of Sciences Knowledge Innovation Project.
Selected Publications(*as the corresponding author, total =39)
1. Q. L. Hou, H. Q. Jiang, X. Zhang, C. Guo, B. Huang, P. Wang, T. P. Wang, K. Y. Wu; J. Li, Z. F. Gong; L. B. Du, Y. Liu, L. Liu, and Chang Chen*.Nitric oxide metabolism controlled by formaldehyde dehydrogenase (fdh, homolog of mammalian GSNOR) plays a crucial role in visual pattern memory in Drosophila. Nitric Oxide: Biology and Chemistry(2011) 24, 17-24.
2. X. Zhang, B. Huang, X. Zhou, andChang Chen*.Quantitative proteomic analysis of S-nitrosated proteins in diabetic mouse liver with ICAT switch method.Protein & Cell(2010) 1(7), 675-87.
3. B. Huang and Chang Chen*.Detection of protein S-nitrosation using irreversible biotinylation procedures (IBP). Free Radic. Biol. Med. (2010) 49, 447–456.
4. X. Zhou, P. Han, J. Li, X. Zhang, B. Huang, and Chang Chen*.ESNOQ, proteomic quantification of endogenous S-nitrosation. PLoS ONE(2010) 5(4): e10015. doi:10.1371/journal.pone.0010015.
5. J. M. Li, Y. Lu, J. H. Zhang, H. Kang, Z. H. Qin,and Chang Chen*. PI4KIIα is a novel regulator of tumor growth via its action on angiogenesis and HIF-1α regulation. Oncogene(2010) 29, 2550-2559.
6. J. Zhuang, T. X. Jiang, D. Lu, Y. T. Luo, C. G. Zheng, J. Feng, D. L. Yang, Chang Chenand X. Y. Yan. NADPH oxidase 4 mediates reactive oxygen species induction of CD146 dimerization in VEGF signal transduction. Free Radic. Biol. Med.(2010) 49, 227-236.
7. P. Wang, G. H. Liu, K. Y. Wu, J. Qu, B. Huang, X. Zhang, X. Zhou, L. Gerace, and Chang Chen*.Repression of classical nuclear export by S-nitrosylation of CRM1.J. Cell Sci.(2009) 122, 3772-3779.
8. S. J. Duan, L. Wan,W. J. Fu, H. Pan, Q. Ding, and Chang Chen, P. W. Han, X. Y. Zhu, L. Y. Du, H. X. Liu, Y. X. Chen, X. M. Liu, X. T. Yan, M. H. Deng, and M. P. Qian. Nonlinear cooperation of p53-ING1-induced bax expression and protein S-nitrosylation in GSNO-induced thymocyte apoptosis: a quantitative approach with cross-platform validation. Apoptosis(2009) 14(2), 236-45.
9. P. W. Han, X. Zhou, B. Huang, X. Zhang, and Chang Chen*，On-gel fluorescent visualization and the site identification of S-nitrosylated proteins. Anal. Biochem.(2008) 377, 150-155.
10. P. W. Han and Chang Chen*.Detergent-free biotin switch combined with LC-MS/MS in analysis of S-nitrosylated proteins. Rapid Commun. Mass Spectrom. (2008) 22(8), 1137-1145.
11. S. J. Duan and Chang Chen*. S-nitrosylation/denitrosylation and apoptosis of immune cells. Cell. Mol. Immunol.(2007) 4 (5), 353－358.
12. J. Qu, G.-H. Liu, K. Y. Wu, P. W. Han, P. Wang, J. M. Li, X. Zhang, and Chang Chen*. Nitric oxide destabilizes Pias3 and regulates sumoylation. PLoS ONE(2007) 2(10): e1085. doi:10.1371/ Journal.pone.0001085.
13. J. Qu., G.-H. Liu, B. Huang, and Chang Chen*.Nitric oxide controls nuclear export of APE1/Ref-1 through S-nitrosation of cysteines 93 and 310. Nucleic Acids Res. (2007) 35, 2522-2532.
14. J. He, T. P. Wang, P. Wang, P. W. Han, and Chang Chen*,A novel mechanism underlying the susceptibility of neuronal cells to nitric oxide: the occurrence and regulation of protein S-nitrosylation is the checkpoint. J. Neurochem.(2007) 102, 1863–1874.
15. B. Huang and Chang Chen*.An ascorbate-dependent artifact that interferes with the interpretation of the biotin switch assay. Free Radic. Biol. Med. (2006) 41, 562–567.
16. J. He, H. J. Kang, F. Yan, andChang Chen*.The endoplasmic reticulum-related events in S-nitrosoglutathione -induced neurotoxicity in cerebellar granule cells.Brain Res.(2004) 1015, 25-33.
17. B. Huang, J. S. Zhang, J. W. Hou, and Chang Chen*.Free radical scavenging efficiency of nano-Se in vitro. Free Radic. Biol. Med.(2003) 35(7), 805-813.
18. Taotao Wei, Chang Chen,Jingwu Hou, Wenjuan Xin and Akitane Mori. Nitric oxide induces oxidative stress and apoptosis in neuronal cells. Biochimica et Biophysica Acta,Mol. Cell Res.(2000)1498, 72-79.
19. Chang Chen, H. R. Tang, L. Sutcliffe, and P. Belton, Green tea polyphenols scavenge 1,1-dipenyl-2- picryl-hydrazyl free radicals in the bilayer of liposomes- Direct evidence from ESR studies. J. Agric.Food Chem.(2000) 8, 5710-5714.
20. Chang Chen, T. Wei, Z. H. Gao, B. Zhao, J. W. Hou, H. Xu, W. J. Xin, and L. Packer. Different effects of the constituents of EGb761 on apoptosis in rat cerebellar granule cells induced by hydroxyl radicals, Biochem. Mol. Biol. Int.(IUBMB Life) (1999) 47, 397-405.
国家发明专利：
1. 特异检测蛋白质或多肽半胱氨酸巯基修饰的方法及其用途，申请号为200910084155.7
2. 肌醇磷脂4位激酶二型α亚型PI4KIIα的应用，申请号为200810104272.0
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