师资队伍 | 陈立功, PhD
陈立功
研究员，博士生导师
陈立功博士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 沙巴体育投注官网助理研究员（PI）并兼任辉瑞（Pfizer）访问科学家. 2013年至今受聘沙巴体育投注官网研究员兼“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
陈立功博士主要研究重要转运蛋白的生理和药理功能，首次发现了多种转运蛋白的内源性底物以及他们在癌症和代谢性疾病中的致病机理以及潜在的药物靶点，2019年分别发现神经外单胺转运蛋白SLC22A3调节白色脂肪组织米色化进而影响机体产热和脑部智力和认知发育重要转运蛋白SLC6A8调节肌酸转运影响巨噬细胞极化和免疫反应；2018年分别发现氨基酸转运蛋白和脂代谢通路在肝癌中的重要功能和潜在治疗途径；2017年与交叉信息沙巴体育合作提出人工智能和机器学习预测药物靶点；2014年提出抑制OCT1治疗脂肪肝新型策略。这些工作均引起广泛关注和引用，多次受到Science, Scientific American和F1000作为研究亮点进行报道；在博士期间，阐述了离子通道GABAA受体拮抗剂的结构和功能活性关系，提出“多样性结构拮抗剂结合同一位点”的假说，获得PNAS高度评价和特别报道。近年来先后担任了国家重大新药创制、国家重大研发计划、国家重大研究计划和比尔盖茨基金会重大项目等多个项目的负责人。并兼任中国药理学会肾脏药理分会常委，中国生物物理学会代谢生物学分会理事，北京市药物代谢学会副主委、北京市药物化学生物学会副主委等。在国际著名期刊Nature Genetics、Immunity、Gut、Hepatology、Nature Communications, PLOS Biology 和 PNAS等发表高水平论文近40篇。
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
荣誉和奖励
1. Outstanding Mentor Award, Tsinghua University (2019)
2. Excellence in Public Service Award in School of Pharmaceutical Sciences, Tsinghua University (2019)
3. National Leading Talents in Science and Technology Innovation (2019)
4. Excellence In Teaching Award of Tsinghua University (2018)
5. WuXi AppTec Prize for Chemical Biology and Pharmacology (2017)
6. Outstanding Mentor of Research Science Initiative (2016-2017)
7. Bayer Young Investigator Award (2015-2018)
8. Janssen Young Investigator Award (2014-2015)
9. Pfizer Therapeutic Innovation Award (2011)
10. Scholarship for QB3 Global Bio-Entrepreneurship, UCSF (2010)
11. UCSF Travel Award (2009)
12. Department Student Award, UC Berkeley (2005)
13. Regents Fellowship, UC Berkeley (2001-2004)
2. Excellence in Public Service Award in School of Pharmaceutical Sciences, Tsinghua University (2019)
3. National Leading Talents in Science and Technology Innovation (2019)
4. Excellence In Teaching Award of Tsinghua University (2018)
5. WuXi AppTec Prize for Chemical Biology and Pharmacology (2017)
6. Outstanding Mentor of Research Science Initiative (2016-2017)
7. Bayer Young Investigator Award (2015-2018)
8. Janssen Young Investigator Award (2014-2015)
9. Pfizer Therapeutic Innovation Award (2011)
10. Scholarship for QB3 Global Bio-Entrepreneurship, UCSF (2010)
11. UCSF Travel Award (2009)
12. Department Student Award, UC Berkeley (2005)
13. Regents Fellowship, UC Berkeley (2001-2004)
代表性论文
1. Liu Q, Sun Z*, Chen L*. Memory T cells: strategies for optimizing tumor immunotherapy. Protein & Cell, 2020, online ahead of print.
2. Hu C, Tao L, Cao X, Chen L*. The solute carrier transporters and the brain: physiological and pharmacological implications. Asian Journal of Pharmaceutical Sciences, 2020,15(2), 131-144 (Cover story).
3. Song W#, Li D#, Tao L, Luo Q, Chen L*. Solute carrier transporters: the metabolic gatekeepers of immune cells. Acta Pharmaceutica Sinica B, 2020, 10(1), 61-78.
4. Che L, Chi W, Qiao Y, Liu Y, Li L, Jia J, Wang J, Cigliano A, Ma Z, Kuang W, Tang Z, Zhang Z, Shui G, Ribback S, Dombrowski F, Osborne TF, Pilo MG, Calvisi DF(*), Chen X(*), Chen L (*). Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans. Gut, 2020, 69 (1), 177-186.
5. Wan F, Zhu Y, Hu H, Dai A, Cai X, Chen L, Gong H, Xia T, Yang D(*), Wang M(*), Zeng J(*). DeepCPI: A Deep Learning-based Framework for Large-scale in silico Drug Screening. Genomics, Proteomics & Bioinformatics, 2019, 17(5), 478-495.
6. Chen L*, Chen X-W*, Huang X*, Wang Y*, Wang Y*, Song B-L*. Regulation of glucose and lipid metabolism in Health and Disease, SCIENCE CHINA Life Sciences, 2019, 62 (11), 1420-1458.
7. Ji L(#), Zhao X(#), Zhang B, Kang L, Song W, Zhao B, Xie W, Chen L(*), Hu X(*). Slc6a8-mediated creatine uptake and accumulation reprogram macrophage polarization via regulating cytokine responses. Immunity, 2019, 51,1-13.
8. Song W(#), Luo Q(#), Zhang Y, Zhou L, Liu Y, Ma Z, Guo J, Huang Y, Cheng L, Meng Z, Li Z, Zhang B, Li S, Yee SW, Fan H, Li P, Giacomini KM(*), Chen L(*)., Organic cation transporter 3 (Oct3) is a distinct catecholamines clearance route in adipocytes mediating the beiging of white adipose tissue. PLOS Biology, 2019,17(1): e2006571. (Highlighted with Press Release “Blocking hormone uptake burns more fat”; Featured Article with Commentary “Fat cells gobbling up norepinephrine”).
9. Zhang Y(#), Zhang Y(#), Sun K, Meng Z, Chen L(*). The SLC transporter in nutrient and metabolic sensing, regulation, and drug development. Journal of Molecular Cell Biology, 2019, 11(1): 1-13. (Featured Article).
10. Cheng L(#), Ge M(#), Lan Z(#), Ma Z, Chi W, Kuang W, Sun K, Zhao X, Liu Y, Feng Y, Huang Y, Luo M, Li L, Zhang B, Hu X, Xu L, Liu X, Huo Y, Deng H, Yang J, Xi Q, Zhang Y, Siegenthaler JA, Chen L(*). Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Archives of Toxicology (Top Journal in toxicological science), 2018, 92(1): 469-485. (Most downloaded article last 6 months).
11. Liu P (#), Ge M (#), Hu J (#), Li X (#), Che L(#), Sun K, Cheng L, Huang Y, Pilo MG, Cigliano A, Pes GM, Pascale RM, Brozzetti S, Vidili G, Porcu A, Cossu A, Palmieri G, Sini MC, Ribback S, Dombrowski F, Tao J, Calvisi DF(*), Chen L(*), Chen X(*). A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis. Hepatology, 2017, 66(1): 167-181.
12. Luo Y (#), Zhao X (#), Zhou J(#), Yang J, Zhang Y, Kuang W, Peng J (*), Chen L(*), Zeng J (*). A network integration approach for drug-target interaction prediction and computational drug repositioning from heterogeneous information. Nature Communications, 2017, 8(1): 573. (Editor’s choice as featured Article).
13. Li C(#), Chen H(#), Lan Z, He S, Chen R, Wang F, Liu Z, Li K, Cheng L, Liu Y, Sun K, Wan X， Chen X, Peng H, Li L, Zhang Y， Jing Y, Huang M, Wang Y, Wang Y, Jiang J, Zha X, Chen L(*), Zhang H(*). mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis. Cell Death & Differentiation, 2019, 26(10), 2015-2028.
14. Wang X(#), Gao H(#), Wu W, Xie E, Yu Y, He X, Li J, Zheng W, Wang X, Cao X, Meng Z, Chen L(*), Min J(*), Wang F(*). The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α‒mediated regulation of Glut2. Protein & Cell, 2018, 10: 436-449.
15. Zhao X, Sun K, Lan Z, Song W, Cheng L, Chi W, Chen J, Huo Y, Xu L, Liu X, Deng H, Siegenthaler JA, Chen L(*). Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity. Scientific Reports, 2017, 7: 46344.
16. Ung PM(#), Song W (#), Cheng L, Zhao X, Hu H, Chen L(*), Schlessinger A(*). Inhibitor discovery for the human GLUT1 from homology modeling and virtual screening. ACS Chemical Biology, 2016, 11(7): 1908-1916.
17. Liang Y, Li S, Chen L(*). The physiological role of drug transporters. Protein & Cell, 2015, 6(5): 334-350.
18. Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA, Li S, Xu L, Keshari KR, Lin MJ, Chien HC, Zhang Y, Morrissey KM, Liu J, Ostrem J, Younger NS, Kurhanewicz J, Shokat KM, Ashrafi K, Giacomini KM(*). OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(27): 9983-9988. (Highlighted by Science and Recommended Article by Faculty 1000).
19. Yee SW(#), Chen L(#), Giacomini KM(*). The role of ATM in response to metformin treatment and activation of AMPK. Nature Genetics, 2012, 44(4): 359-360. (Co-first author).
20. Chen L, Durkin KA, Casida JE(*). Spontaneous mobility of GABAA receptor M2 extracellular half relative to noncompetitive antagonist action. Journal of Biological Chemistry, 2006, 281(50): 38871-38878.
21. Chen L, Durkin KA, Casida JE(*). Structural model for gamma-aminobutyric acid receptor noncompetitive antagonist binding: widely diverse structures fit the same site. Proceedings of the National Academy of Sciences of the United States of America, 2006, 103(13): 5185-5190. (Highlighted Article with Commentary in PNAS).
2. Hu C, Tao L, Cao X, Chen L*. The solute carrier transporters and the brain: physiological and pharmacological implications. Asian Journal of Pharmaceutical Sciences, 2020,15(2), 131-144 (Cover story).
3. Song W#, Li D#, Tao L, Luo Q, Chen L*. Solute carrier transporters: the metabolic gatekeepers of immune cells. Acta Pharmaceutica Sinica B, 2020, 10(1), 61-78.
4. Che L, Chi W, Qiao Y, Liu Y, Li L, Jia J, Wang J, Cigliano A, Ma Z, Kuang W, Tang Z, Zhang Z, Shui G, Ribback S, Dombrowski F, Osborne TF, Pilo MG, Calvisi DF(*), Chen X(*), Chen L (*). Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans. Gut, 2020, 69 (1), 177-186.
5. Wan F, Zhu Y, Hu H, Dai A, Cai X, Chen L, Gong H, Xia T, Yang D(*), Wang M(*), Zeng J(*). DeepCPI: A Deep Learning-based Framework for Large-scale in silico Drug Screening. Genomics, Proteomics & Bioinformatics, 2019, 17(5), 478-495.
6. Chen L*, Chen X-W*, Huang X*, Wang Y*, Wang Y*, Song B-L*. Regulation of glucose and lipid metabolism in Health and Disease, SCIENCE CHINA Life Sciences, 2019, 62 (11), 1420-1458.
7. Ji L(#), Zhao X(#), Zhang B, Kang L, Song W, Zhao B, Xie W, Chen L(*), Hu X(*). Slc6a8-mediated creatine uptake and accumulation reprogram macrophage polarization via regulating cytokine responses. Immunity, 2019, 51,1-13.
8. Song W(#), Luo Q(#), Zhang Y, Zhou L, Liu Y, Ma Z, Guo J, Huang Y, Cheng L, Meng Z, Li Z, Zhang B, Li S, Yee SW, Fan H, Li P, Giacomini KM(*), Chen L(*)., Organic cation transporter 3 (Oct3) is a distinct catecholamines clearance route in adipocytes mediating the beiging of white adipose tissue. PLOS Biology, 2019,17(1): e2006571. (Highlighted with Press Release “Blocking hormone uptake burns more fat”; Featured Article with Commentary “Fat cells gobbling up norepinephrine”).
9. Zhang Y(#), Zhang Y(#), Sun K, Meng Z, Chen L(*). The SLC transporter in nutrient and metabolic sensing, regulation, and drug development. Journal of Molecular Cell Biology, 2019, 11(1): 1-13. (Featured Article).
10. Cheng L(#), Ge M(#), Lan Z(#), Ma Z, Chi W, Kuang W, Sun K, Zhao X, Liu Y, Feng Y, Huang Y, Luo M, Li L, Zhang B, Hu X, Xu L, Liu X, Huo Y, Deng H, Yang J, Xi Q, Zhang Y, Siegenthaler JA, Chen L(*). Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Archives of Toxicology (Top Journal in toxicological science), 2018, 92(1): 469-485. (Most downloaded article last 6 months).
11. Liu P (#), Ge M (#), Hu J (#), Li X (#), Che L(#), Sun K, Cheng L, Huang Y, Pilo MG, Cigliano A, Pes GM, Pascale RM, Brozzetti S, Vidili G, Porcu A, Cossu A, Palmieri G, Sini MC, Ribback S, Dombrowski F, Tao J, Calvisi DF(*), Chen L(*), Chen X(*). A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis. Hepatology, 2017, 66(1): 167-181.
12. Luo Y (#), Zhao X (#), Zhou J(#), Yang J, Zhang Y, Kuang W, Peng J (*), Chen L(*), Zeng J (*). A network integration approach for drug-target interaction prediction and computational drug repositioning from heterogeneous information. Nature Communications, 2017, 8(1): 573. (Editor’s choice as featured Article).
13. Li C(#), Chen H(#), Lan Z, He S, Chen R, Wang F, Liu Z, Li K, Cheng L, Liu Y, Sun K, Wan X， Chen X, Peng H, Li L, Zhang Y， Jing Y, Huang M, Wang Y, Wang Y, Jiang J, Zha X, Chen L(*), Zhang H(*). mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis. Cell Death & Differentiation, 2019, 26(10), 2015-2028.
14. Wang X(#), Gao H(#), Wu W, Xie E, Yu Y, He X, Li J, Zheng W, Wang X, Cao X, Meng Z, Chen L(*), Min J(*), Wang F(*). The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α‒mediated regulation of Glut2. Protein & Cell, 2018, 10: 436-449.
15. Zhao X, Sun K, Lan Z, Song W, Cheng L, Chi W, Chen J, Huo Y, Xu L, Liu X, Deng H, Siegenthaler JA, Chen L(*). Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity. Scientific Reports, 2017, 7: 46344.
16. Ung PM(#), Song W (#), Cheng L, Zhao X, Hu H, Chen L(*), Schlessinger A(*). Inhibitor discovery for the human GLUT1 from homology modeling and virtual screening. ACS Chemical Biology, 2016, 11(7): 1908-1916.
17. Liang Y, Li S, Chen L(*). The physiological role of drug transporters. Protein & Cell, 2015, 6(5): 334-350.
18. Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA, Li S, Xu L, Keshari KR, Lin MJ, Chien HC, Zhang Y, Morrissey KM, Liu J, Ostrem J, Younger NS, Kurhanewicz J, Shokat KM, Ashrafi K, Giacomini KM(*). OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(27): 9983-9988. (Highlighted by Science and Recommended Article by Faculty 1000).
19. Yee SW(#), Chen L(#), Giacomini KM(*). The role of ATM in response to metformin treatment and activation of AMPK. Nature Genetics, 2012, 44(4): 359-360. (Co-first author).
20. Chen L, Durkin KA, Casida JE(*). Spontaneous mobility of GABAA receptor M2 extracellular half relative to noncompetitive antagonist action. Journal of Biological Chemistry, 2006, 281(50): 38871-38878.
21. Chen L, Durkin KA, Casida JE(*). Structural model for gamma-aminobutyric acid receptor noncompetitive antagonist binding: widely diverse structures fit the same site. Proceedings of the National Academy of Sciences of the United States of America, 2006, 103(13): 5185-5190. (Highlighted Article with Commentary in PNAS).
BOOK CHAPTER
Huang SM, Chen L, Giaocmini KM, Pharmacogenomic Mechanism of Drug Toxicity. The Principle of Clinical Pharmacology (3rd edition), Chapter 17.
专利
1. Chen L, Cheng L, Liang Y, Li Y, Wang J, Lang M. A method for preparation of metformin based photoaffinity labeling probes as a strong AMPK activator (Patent No.: 201710564476.1).
2. Chen L, Sun Z, Zhao H, Cai J, Ma J, Guo X, Qi H, Xue Q, Zhang S. Application of memory lymphocytes in the treatment of liver cancer (Patent No.: 201910068937.5).
3. Huang Y, Xu Q, Bien-Ly N, Weisgraber L, Chen L, Peters-Libeu C. Antibody specific for apolipoprotein and methods of use thereof (Patent No.: US 09102717).
