科学研究 | 肖百龙 博士

肖百龙博士

博士

肖百龙博士自2013年1月起在清华大学药学院(原医学院药学系)、清华-北大生命科学联合中心、IDG/麦戈文脑科学研究所担任研究员、博士生导师,是青年千人计划、基金委优秀科学基金获得者。他于2001年从中山大学生命科学学院生物化学专业获得理学学士学位。2001-2006年期间就读于加拿大卡尔加里大学(University of Calgary)并获得心血管分子生物学专业博士学位,导师是Wayne Chen教授。2007-2012年期间在美国斯克里普斯研究所(The Scripps Research Institute)从事神经科学博士后研究,主要开展触觉痛觉分子细胞学机制的研究工作,导师是Ardem Patapoutian教授。


研究方向

离子通道是控制细胞兴奋性和其它功能的一类重要跨膜蛋白。遗传突变或生理调节性紊乱所导致的离子通道功能失调可以致使包括神经疾病、心血管病、免疫疾病及代谢疾病等在内的很多重大疾病(统称为离子通道病)。因而,对于离子通道的结构和功能的研究不仅有助于我们了解这一类重要蛋白,并有助于相关新药或新疗法的设计开发。
我们实验室综合利用分子生物学、生物化学、结构生物学、生物物理学、神经生物学、钙成像技术、电生理、基因敲除小鼠的建立和行为学测试、高通量靶点或药物筛选等研究手段,
着重开展温度门控型以及机械力门控型离子通道(例如机械力门控Piezo离子通道)的鉴定发现、结构功能关系以及生理学和病理学意义的研究。这类被称之为感受性的离子通道可以作为包括温度、化学物质及其机械力等触觉刺激的受体从而对控制我们五感之一的触觉的发生和调控以及其它机械力传感生理过程具有极其重要的作用。通过对这些离子通道的研究,我们期望能对触觉和痛觉的分子生物学机制以及机械力传感在其它生理过程中的作用能有更好的了解,并期望最终能开发出以这些通道为靶点的新型药物。
实验室目前的主要研究方向包括:1)机械门控Piezo离子通道结构功能、生理/病理学意义、药物筛选;
2)STIM1/Orai离子通道温度敏感性的生理学意义;3)签定发现新型机械门控或温度门控离子通道或受体。

科学贡献

肖百龙博士在过去15年以来一直致力于鉴定发现具有重要生理学功能的离子通道、并对其结构功能关系以及其在正常与病理下的生理功能进行研究,积累了丰富的离子通道理论知识和研究经验。目前已经累计在Nature, Neuron, Nature Chemical Biology, Nature Neuroscience, Journal of Neuroscience, Circulation Research, PNAS, Journal of Biological Chemistry, Biochemical Journal等一系列SCI国际刊物累计发表23篇科研论文,其中2篇为通讯作者(含共同通讯作者)文章、10篇为第一作者(含共同第一作者)文章。所有文章总SCI它引用1700余次,一作文章总它引900余次。其中以共同第一作者身份于2012年发表在《自然》杂志的论文在web of science上被列为高引用论文,ESI它引次数排名1%。

研究成果

1.首次鉴定了机械门控Piezo1离子通道的负责离子通透与选择性的孔径区模块以及负责机械力感受与传感的机械力传感模块,揭示了其离子通透及机械力传感的分子基础。该成果以长文形式 (article) 于2016年发表在神经科学顶级期刊《神经元》杂志 (Zhao et al., Neuron 2016)。


2.次解析小鼠全长机械力门控Piezo1离子通道的冷冻电镜三维结构,为深入理解这类全新离子通道家族的结构特点、离子流通和选择性机制、机械力门控机制等提供了重要线索。该成果以长文形式 (article) 于2015年发表在国际顶级期刊《自然》杂志 (Ge et al., Nature 2015)。



3.首次证实在序列和结构上高度复杂的Piezo蛋白是在哺乳动物中签定发现的首类机械门控阳非选择性阳离子通道的孔道蛋白,确立Piezo蛋白作为一类全新的离子通道家族。该成果以长文形式 (article) 于2012年发表在《自然》杂志 (Coste and Xiao et al., Nature 2012), 并被web of science评为1%高被引论文。



4.首次发现STIM1/Orai1可以作为一类新型温度激活离子通道。该成果以长文形式 (article) 于2011年发表在《自然》杂志子刊《自然-化学生物学》 (Xiao et al., Nature Chemical Biology 2011),并被《科学》杂志子刊《科学-信号传导》(Science Signaling)评为2011年信号传导研究领域的年度突破。


荣誉及获奖

中组部青年千人,自然科学基金优秀青年科学基金,清华大学Bayer Investigator Fellowship,
清华大学Janssen Fellowship。

发表论文
 

1.Qiancheng Zhao, Kun Wu, Jie Geng, Shaopeng Chi, Yanfeng Wang, Peng Zhi, Mingmin Zhang, Bailong Xiao# (2016). Ion Permeation and Mechanotransduction Mechanisms of Mechanosensitive Piezo Channels. Neuron. 2016 Mar 16;89(6):1248-63. (Previewed by Neuron; Highlighted by Neuroscience Bulletin; News report by EurekAlert).
2.Jingpeng Ge (co-first), Wanqiu Li (co-first), Qiancheng Zhao (co-first), Ningning Li (co-first), Maofei Chen, Peng Zhi, Ruochong Li, Ning Gao#, Bailong Xiao#, Maojun Yang# (2015). Architecture of the mammalian mechanosensitive Piezo1 channel. Nature. 2015 Nov 5;527(7576):64-9. doi: 10.1038/nature15247. Epub 2015 Sep 21. (# Co-corresponding author).
3.Bertrand Coste (co-first), Bailong Xiao (co-first), Jose S. Santos, Ruhma Syeda, Jorg Grandl, Kathryn S. Spencer, Sung Eun Kim, Manuela Schmidt, Jayanti Mathur, Adrienne E. Dubin, Mauricio Montal, Ardem Patapoutian (2012). Piezo Proteins Are Pore-forming Subunits of Mechanically Activated Channels. Nature. 2012 Feb 19;483(7388):176-81 PMID:22343900 (Highly cited paper; Selected by Faculty of 1000; Featured by Nature News & Views; TSRI News & Views; Reported by Science Daily)
4.Bailong Xiao, Bertrand Coste, Jayanti Mathur, Ardem Patapoutian (2011). Temperature-dependent STIM1 activation induces Ca2+ influx and modulates gene expression. Nat Chem Biol. 2011 Jun;7(6):351-8. PMID: 21499266 (Nominated for 2011 signaling breakthroughs of the year by Science Signaling; Featured by Nat Chem Biol. News & Views; Featured by TSRI News & Views; Reported by Science Daily)
5.Bailong Xiao, Ardem Patapoutian (2011). Scratching the surface: a role of pain-sensing TRPA1 in itch. Nat Neurosci. 2011 May;14(5):540-2. PMID: 21522144 News & Views
6.Bailong Xiao, Adrienne E. Dubin, Badry Bursulaya, Veena Viswanath, Timothy J. Jegla, Ardem Patapoutian (2008). Identification of Transmembrane Domain Five as a Critical Molecular Determinant of Menthol Sensitivity in Mammalian TRPA1 Channels. J Neurosci. 2008 Sep 24;28(39):9640-51.
7.Lindsey J. Macpherson (co-first), Bailong Xiao (co-first), Kelvin Y. Kwan (co-first), Matt J. Petrus, Adrienne E. Dubin, SunWook Hwang, Benjamin Cravatt, David P. Corey, Ardem Patapoutian (2007). An Ion Channel Essential for Sensing Chemical Damage. J Neurosci. 2007 Oct 17;27(42):11412-5.
8.Bailong Xiao, Xixi Tian, Wenjun Xie, Peter P. Jones, Shitian Cai, Xianhua Wang, Dawei Jiang, Lin Zhang, Keyun Chen, Michael P. Walsh, Heping Cheng, and S. R. Wayne Chen (2007). Functional Consequence of PKA-dependent Phosphorylation of the Cardiac Ryanodine Receptor: Sensitization of Store-overload-induced Ca2+ release (SOICR). J Biol Chem. 2007 Aug 10.
9.Bailong Xiao, Guofeng Zhong, Masakazu Obayashi, Dongmei Yang, Michael P. Walsh, Yakhin Shimoni, Heping Cheng, Henk ter Keurs, and S. R. Wayne Chen (2006). Serine-2030, but not Serine-2808, is the Major RyR2 Phosphorylation Site Responding to PKA Activation upon beta-adrenergic Stimulation in Normal and Failing Hearts. Biochem J. 2006 Feb 17. (Commented by editorial)
10.Bailong Xiao, Ming Tao Jiang, Mingcai Zhao, Dongmei Yang, Cindy Sutherland, F. Anthony Lai, Michael P. Walsh, Heping Cheng, David C. Warltier, and S. R. Wayne Chen (2005). Characterization of a Novel Protein Kinase A Phosphorylation Site, Serine-2030, Reveals No PKA Hyperphosphorylation of the Cardiac Ryanodine Receptor in Canine Heart Failure. Circ Res. 2005 Apr 29;96(8):847-55.
11.Bailong Xiao, Cindy Sutherland, Michael P. Walsh, S. R. Wayne Chen (2004). Protein Kinase A Phosphorylation at Serine-2808 of the Cardiac Ca2+-Release Channel (Ryanodine Receptor) Does Not Dissociate 12.6-kDa FK506-Binding Protein (FKBP12.6). Circ Res. 2004 Mar 5;94(4):487-95.
12.Bailong Xiao, Haruko Masumiya, Dawei Jiang, Ruiwu Wang, Yoshitatsu Sei, Lin Zhang, Takashi Murayama, Yasuo Ogawa, F. Anthony Lai, Terence Wagenknecht, and S. R. Wayne Chen (2002). Isoform Dependent Formation of Heteromeric Ca2+ Release Channels (Ryanodine Receptors). J Biol Chem. 2002 Nov 1; 277(44): 41778-85. (Selected by Faculty of 1000)
13.Adrienne E. Dubin, Manuela Schmidt, Jayanti Mathur, Matt J. Petrus, Bailong Xiao, Bertrand Coste, Ardem Patapoutian. Inflammatory signals enhance piezo2-mediated mechanosensitive currents. Cell Rep. 2012 Sep 27;2(3):511-7.Epub 2012 Aug 23. PMID: 22921401
14.Peter P. Jones, Xing Meng, Bailong Xiao, Shitian Cai, Jeff Bolstad, Terence Wagenknecht, Zheng Liu and S. R. Wayne Chen (2008). Localization of PKA phosphorylation site, Ser2030, in the three-dimensional structure of cardiac ryanodine receptor. Biochem J. 2008 Mar 1;410(2):261-70.
15.Xing Meng, Bailong Xiao, Shitian Cai, Xiaojun Huang, Fei Li, Jeff Bolstad, Ramon Trujillo, Judith Airey, S. R. Wayne Chen, Terence Wagenknecht, and Zheng Liu (2007). Three-Dimensional Localization of Serine 2808, a Phosphorylation Site in Cardiac Ryanodine Receptor. J Biol Chem. 2007 Aug 31;282(35):25929-39.
16.Dongmei Yang, Wei-Zhong Zhu, Bailong Xiao, Didier X. P. Brochet, S. R. Wayne Chen, Edward G. Lakatta, Rui-Ping Xiao and Heping Cheng (2007). Ca2+/calmodulin kinase II-dependent Phosphorylation of Ryanodine Receptors Suppresses Ca2+ Sparks and Ca2+ Waves in Cardiac Myocytes. Circ Res. 2007 Feb 16;100(3):399-407.
17.Masakazu Obayashi, Bailong Xiao, Bruno D. Stuyvers, Allen W. Davidoff, Jie Mei, S.R. Wayne Chen, Henk E.D.J. ter Keurs (2006). Spontaneous diastolic contractions and phosphorylation of the cardiac ryanodine receptor at serine-2808 in congestive heart failure in rat. Cardiovasc Res. 2006 Jan;69(1):140-51.
18.Dawei Jiang, Ruiwu Wang, Bailong Xiao, Huihui Kong, Philip Choi, Lin Zhang, and S. R. Wayne Chen (2005). Enhanced Store Overload Induced Ca2+ Release (SOICR) and Channel Sensitivity to Luminal Ca2+ Activation is a Common Defect of RyR2 Mutations Linked to Ventricular Tachycardia and Sudden Death. Circ Res. 2005 Nov 25;97(11):1173-81. (Commented by editorial)
19.Dawei Jiang, Bailong Xiao, Dongmei Yang, Ruiwu Wang, Philip Choi, Lin Zhang, Heping Cheng, and S. R. Wayne Chen  (2004). Ryanodine Receptor Mutations Associated with Ventricular Tachycardia and Sudden Cardiac Death Reduce the Threshold for Store Overload Induced Ca2+ Release (SOICR). Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):13062-7.
20.Dawei Jiang, Bailong Xiao, Xiaoli Li, and S. R. Wayne Chen (2003). Smooth Muscle Tissues Express a Major Dominant-Negative Splice Variant of the Type 3 Ca2+ Release Channel (Ryanodine Receptor) J Biol Chem. 2003 Feb 14; 278(7): 4763-9. (Selected by Faculty of 1000)
21.Haruko Masumiya, Ruiwu Wang, Jing Zhang, Bailong Xiao, S. R. Wayne Chen (2003) Localization of the 12.6-kDa FK506-binding protein (FKBP12.6) binding site to the NH2-terminal domain of the cardiac Ca2+ release channel (ryanodine receptor). J Biol Chem. 2003 Feb 7; 278(6): 3786-92.
22.Dawei Jiang, Bailong Xiao, Lin Zhang, S. R. Wayne Chen (2002). Enhanced Basal Activity of a Cardiac Ca2+ Release Channel (Ryanodine Receptor) Mutant Associated With Ventricular Tachycardia and Sudden Death. Circ Res. 9; 91(3): 218-25. (Commented by editorial)