科学研究 | 陈立功 博士

陈立功博士

清华大学药学院研究员

陈立功博士2013 年入选第四批国家千人计划(青年项目)。1997年获得南开大学化学学士学位;2006 年从加州大学伯克利分校(UC Berkeley)获得化学生物学博士学位;2007-2011 年加入旧金山加州大学(UCSF)进行博士后研究;2012 年至2013 年担任UCSF 药学院助理研究员(PI)并兼任辉瑞(Pfizer)访问科学家. 2013年至今受聘清华大学研究员兼“生物治疗协同创新中心”研究员。


研究方向

溶质载体  (SLCs) 转运蛋白组成了最大的跨膜运输蛋白家族。 SLCs 在生物膜上调节运输无机离子、核苷酸、氨基酸、神经递质、糖、嘌呤、脂肪酸及多种药物分子,它们参与外源性物质和生理性化合物的小肠吸收,肝脏、肾脏排泄以及大脑和心脏内多种生理性物质的器官内平衡和分布。多项全基因组关联研究(GWAS)表明,SLC转运蛋白编码基因的突变与多种疾病易感性相关,如多种癌症、冠状动脉硬化、原发性系统性肉碱缺乏症、特发性肾性低尿酸血症、克罗恩氏病和痛风等,这些研究结果提示该家族转运蛋白有着重要的生理角色和作为潜在药物靶点的可能。陈立功实验室集中在重要溶质载体  (SLCs) 转运蛋白的生理和药理功能上,运用多种现在分子和细胞生物学手段研究它们与疾病发生的关系和作为药物标靶的潜在开发作用。
 
药物毒性是限制药物研发的关键因素之一,陈立功实验室另外一个研究重点是研究代表性药物的毒性分子机理,进而为设计安全和有效的药物奠定分子基础。
 

科学贡献

主要从事转运蛋白生理学、药理学和药物遗传学研究,利用代谢组学、基因剔除和转基因技术,第一次作用利用系统药理学证实了1型有机阳离子转运蛋白(OCT1)的生理底物是维他命B1 (Vitamin B1),并运用了一系列的分子细胞生物学手段阐释了它的在糖尿病和脂肪肝的致病机理中的作用,Science作为研究亮点进行了报道;首次证实了3 型有机阳离子转运蛋白(OCT1/3)在肌肉中输运抗2型糖尿病药物二甲双胍中的作用。并与美国食物与药品监督管理局(FDA)药物评估中心合作撰写了《临床药理学原理》一书。博士期间主要从事氨基丁酸受体和其拮抗剂药理和毒研究。利用蛋白质工程对氨基丁酸受体拮抗剂结合测定,蛋白质三维结构模型阐述了结构多样化的拮抗剂结合在共同的位点,获得PNAS高度评价和特别报道。

研究成果

针对脂肪肝开发治疗性单体克隆抗体包括生物活性验证,人源化的小鼠脂肪肝模型
有机正离子转运蛋白1 是维他命B1转运蛋白及其在肝细胞中的脂肪代谢和糖代谢研究
有机正离子转运蛋3在抗二型糖尿病药物的动力学和药效的体内体外研究
结构和功能关系研究,氨基丁酸受体和其对抗剂相互作用
确定氯离子通道/氨基丁酸受体的离子通道结构利用蛋白工程方法

AWARDS

1. Tsinghua-Janssen Investigator Award, 2014
2. National 1000 Talent Program (Youth), CHINA, 2013
3. Therapeutic Innovation Award from Pfizer (2011)
4. Scholarship for QB3 Global Bio-Entrepreneurship, QB3-UCSF (2010)
5. UCSF Travel Award (2009)
6. Department Student Award, University of California at Berkeley (2005)
7. Regents Fellowship, University of California at Berkeley (2001-2004)
 


Selected Publications

1. Liang Y, Chen L#. The Physiological role of drug transporters. Protein & Cell, 2014,In Press
2. Chen L#, Yee SW, Giacomini KM#. The drug transporter physiologically important. Cell Cycle, 2014, In press
3. Chen L, Shu Y, Liang X, et al. OCT1 is a high capacity thiamine transporter regulating hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A. 2014, 111: 9983-8. (Direct Submission, High-lighted by Science and F1000 Primer)
4. Yee SW*, Chen L*, Giacomini KM. The role of ATM in response to metformin treatment and activation of AMPK. Nature Genetics. 2012 44:359-60. (*Contribute equally)
5. Chen L, Hong C, Chen EC, et al. Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3. Pharmacogenomics Journal. 2012 (PMID: 22231567).
6. Chen L, Xue L, Giacomini KM, John E. Casida. GABAA receptor open-state conformation determines non-competitive antagonist binding. Toxicology and applied pharmacology 2011, 250: 221-8.
7. Chen L, Pawlikowski B, Schlessinger A, et al. Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenetics and Pharmacogenomics 2010, 20: 687-99.
8. Chen L, Takizawa M, Chen E, et al. Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function. Journal Pharmacology and Experimental Therapeutics. 2010, 335:42-50.
9. Chen L, Durkin K, Casida JE. Spontaneous mobility of GABAA receptor M2 extracellular half relative to noncompetitive antagonist action. Journal of Biological Chemistry. 2006, 281: 38871-8.
10. Chen L, Durkin K, Casida JE. Structural model for GABA receptor noncompetitiveantagonist binding: widely-diverse structures fit the same site. Proceedings of the National Academy of Sciences USA 2006, 103: 5185-10. (See commentary in Proc Natl Acad Sci U S A. 2006, 18; 103: 6081-2).
11. Ahlin G, Chen L, LazorovaL, et al. Genotype dependent effects of inhibitors of the organic cation transporter, OCT1: Predictions of metformin interactions. Pharmacogenomics Journal. 2011, 11: 400-11.
12. Yee SW, Chen L, Giacomini KM. Pharmacogenomics of drug transporters: past, present and future. Pharmacogenomics. 2010,11: 475-9.
13. More SS, Li S, Yee SW, Chen L, et al (2010) Organic cation transporters modulate the uptake and cytotoxicity of picoplatin, a third generation platinum analog. Molecular Cancer Therapeutics. 2010, 9: 1058-69.
14. Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan Chen L, and Huang Y. Apolipoprotein E4 causes Tau-dependent hilar GABAergic interneuron impairment, leading to learning and memory deficits in mice. Journal of Neuroscience 2010, 30: 13707-17.
15. Hesselson SE, Matsson P, Shima JE, Fukushima H, Yee SW, Kobayashi Y, Gow JM, Ha C, Ma B, Poon A, Johns SJ, Stryke D, Castro RA, Tahara H, Choi JH, Chen L, et al. Genetic variation in the proximal promoter of ABC and SLC superfamilies: liver and kidney specific expression and promoter activity predict variation. PLoS One. 2008, 4: e6942
16. Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman MK, Urban TJ, Chen L, et al. (2009) Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenetics and Genomics. 2009, 19: 497-504.
 

BOOK CHAPTER

Huang SM, Chen L, Giaocmini KM, Pharmacogenomic Mechanism of Drug Toxicity. The Principle of Clinical Pharmacology (3rd edition), Chapter 17. (Center for Drug Evaluation and Research, FDA, USA).
 

PATENT

Huang Y, Xu Q, Bien-Ly N, Weisgraber L, Chen L, Peters-Libeu C. Agents that Detect a Unique Conformation of ApoE and Methods of Use Thereof (U.S. Application Serial No. 61/309,280)