韩源平教授

英文版


      
联系方式: hanyp@scu.edu.cn 或 southcalyph@gmail.com 

1, 个人简介
    韩源平 (Yuan-Ping Han,Ph.D.),博士。在美国学习工作二十年后,作为海外人才引进人才,
    现任四川大学生命科学学院教授。研究领域主要在组织损伤,修复,纤维化,肝硬化,以及代谢综合症。
    作为美国南加州大学(University of Southern California)博士导师, 他的研究得到National
     Institutes of Health多个基金的支持, 包括两个R01, 共$2.7 million 以及其它基金。他
     是美国NIH, NSF, 欧洲Wellcome Foundation的基金评委。为多个专业期刊, 如Hepatology, 
    Am J Pathology, J Biological Chemistry, J of Immunology审稿。在肝脏方面, 主要从
    事肝星状细胞及肝硬化,以及脂肪肝(NASH)研究。在皮肤方面,主要研究伤口愈合,溃疡,瘢痕的
    细胞机理。在代谢综合症方面强调系统生物学的发病机理。近年来,也从事新药物的开发研究。研究
    方法涉及分子生物学,生物化学,组织及细胞生物学,免疫学,人体生理及病理学的整合,转化,
    及临床应用。发表了三十多篇SCI文章。

2, 教育经历
    1978-1982, 四川大学, 生物系, 主修生物化学, 学士学位
    1990-1996, 西奈山医学院 (The Mount Sinai School of Medicine, New York), 主修生物医学科学
                (Biomedical Science), 获哲学博士学位 ,PhD, 导师, Dr. Ronald A. Kohanski
    1996-1999, 南加大洛杉矶儿童医院Los Angeles Children’s Hospital/University of Southern California, 
                做博士后 (1996-1999), 导师, Dr. Yun-Kai (Teddy) Fong

3,研究工作经历
    1982-1985, 地质矿产部工艺研究所, 助理研究员
    1985-1989, 四川抗菌素研究所, 助理研究员
    1989-1990, SmithKline Pharmaceuticals (SKF, 美国, 费城), 从事新药发现研究
    2000-2003, 南加州大学 University of Southern California, Keck School of Medicine, 助理研究员
    2004-2007, 南加州大学 University of Southern California, Keck School of Medicine,研究助理教授
    2007-2011, 南加州大学 University of Southern California, Keck School of Medicine, 助理教授 
                (Assistant Professor at Tenure Track)。 USC Keck School of Medicine, PIBBS 
                博士研究生导师。USC Department of Pathology 硕士研究生导师。
    2004年-现在,南加州大学,Keck School of Medicine, 酒精肝病及胰腺疾病研究中心会员
    2011-至今, 四川大学生命科学学院教授, 首都医科大学北京佑安医院客座教授


四、研究领域及成果。

    (1) 代谢综合症,脂肪肝,肥胖的机理及新疗法的开发。
    近年来我们将工作的重点的一部分转移到代谢综合症,脂肪肝,肥胖的机理研究及新药物的开发。随
    着社会经济的巨大发展,代谢综合症(Metabolic Syndrom,MS) 表现为高血脂,脂肪肝,肥胖,
    糖尿病,呈蔓延之势。近来官方的统计,中国有1亿六千万人群患有不同程度的代谢综合症。在西方,
    四分之一的成人为肥胖。代谢综合症的危险性在于引发糖尿病,心血管疾病,及脑中风,已成为最主
    要的死亡杀手。代谢综合症的发生与高糖,高脂肪饮食有密切关系。改善饮食及生活方式是治疗代谢
    综合症的有效方法。在药物治疗方法,降胆固醇,降高血压,降血糖是主要的策略。另外,使异位的
    脂肪(腹内)回归到脂肪皮下细胞,也是防治代谢综合症的新方向。基于多年来我们在慢性疾病研究
    的经验,我们采用系统生物学的方法,从新的角度及方法来研究代谢综合症。代谢综合症的发生分为
    三个阶段。第一步,高脂肪,高果糖饮食引起的肠道菌群(microbiota)的改变,造成血液内毒素的
    上升及腹部脂肪组织的慢性炎症。第二步,慢性炎症造成胰岛素抵抗,糖耐受,II型糖尿病。作为弥
    补机制,高血糖在肝脏转化为脂肪酸,形成高血脂,脂肪肝。而脂肪肝及腹内脂肪产生的炎症会造成
    肝脏损伤,导致高密度脂蛋白(HDL)下降,凝血机制增强。第三步,持续的糖尿病,高血脂,凝血
    异常,将产生心血管阻塞,中风,加速死亡。为此,我们以系统生物学的方法,从营养成分及维生素
    的作用,肠道菌群的改变,肠道及腹内脂肪,肝脏,胰腺的炎症及损伤,以及内分泌,外分泌的改变
    来阐述代谢综合症的发生机理。同时,基于我们近年来的发现,我们正在研究,开发全新的药物,用
    于代谢综合症的预防及治疗。

    (2)组织纤维化的细胞生物学。
    在美国南加大(University of Southern California)工作期间,作为PI并在两个NIH R01基
    金的资助下,我们长期从事这方面的研究。广义的组织损伤包括病毒感染,污染毒物的摄入,及多种
    慢性疾病,肿瘤等等。损伤以后,肌体有两种选择,是再生,还是修复。大多数的组织仅有极小的再
    生能力(例如肝脏,皮肤)。而采用修复是大规模或是持续损伤的首要选择。修复的主要特征是产生
    纤维化的组织结构。作为进化的选择结果,组织纤维化对于肌体是有益的,它为失去的组织打上了
    “补丁”,否则因失去的组织,个体不能幸存。但是,持续的纤维化将使得慢性疾病,例如肿瘤得以持
    续。器官的老年衰竭也是组织纤维化的结果。据估计,大约50%的死亡都与组织纤维化有关。大多数
    的肿瘤之所以能够持续的原因,在很大程度上是因为纤维化组织为肿瘤提供了生长的环境。我们的工
    作主要集中于肝星状细胞 (hepatic stellate cells) 的转分化(trans-differentiation)。
    我们发现在肝星状细胞转分化过程中,多个MMP基因被不可逆地关闭,消静(silencing)。我们认为,
    在正常肝血窦中星状细胞的表型是有其3维ECM通过表观遗传(epigenetic control) 所决定的。
    更进一步,根据我们的发现,我们认为3D ECM通过下调II-型HDAC,使MMP基因群(mmp loci) 处
    于表观遗传水平的开放状态,在炎症因子引发的信号传导下,能够大量表达,释放生长因子,开启损
    伤及修复。星状细胞在生长因子的促动下转化为肌成纤维母细胞(myofibroblasts), 并形成纤维
    组织。MMP基因在肌成纤维母细胞的消静,将促进ECM的积累以及纤维化。我们发现,在星状细胞转分
    化过程中,II-型HDAC趋于上升,蛋白质稳定,导致MMP基因被抑制。我们将继续回答以下问题:
    (1)MMP基因群的表观遗传景观在转分化过程中的改变,从开放到抑制?(2)II-型HDAC的降解酶,
    以及在纤维化中的作用?(3)3D ECM对II-型HDAC的调控以及在损伤中MMP基因的表达。

    (3)肝纤维化中的免疫耐受。
    肝纤维化不但是由于星状细胞的转分化及肌纤维母细胞的形成,同样重要的是肝硬化所处的免疫赖受
    的宏观环境(macro-environment of immune tolerance),使得纤维组织免于被清除,逃逸免
    疫监控 (escaping from immune surveillance)。同时,免疫赖受也为肿瘤生长,转移,恶化
    提供环境条件。在前期工作中,我们发现天然调节性T细胞(naturally occurring Tregs, nTres) 
    在肝损伤中的下降是由于其细胞凋亡所致,而在肝修复过程中产生的诱导型Tregs(induced Tregs, iTregs)
    是由于MMP激活的TGFbeta从而诱道Foxp3所致。该工作近来被Journal of Molecular Cell Biology 
    (影响因子: 7.3) 接受。我们发现伴随肝纤维化的形成,Tregs聚集于纤维桥附近,说明Tregs产生
    的免疫赖受可能促进纤维化的持续。当我们用单抗干预Tregs时,发现能够促进小鼠肝硬化的消融,
    表明Tregs可能抑制纤维的消融。我们发现Tregs通过上调TIMP来抑制MMP。同时,我们在肝硬化病
    人的肝组织中检出Tregs的升高,说明可能的因果关系。为此,我们提出新的假设:肝星状细胞所释
    放的MMP通过激活TGFbeta,并且在IL1作用下释放维甲酸(retinoic acid)来诱导Tregs,使纤
    维化免于被清除。另一方面,与北京佑安医院合作,我们也对II-型巨噬细胞(alternatively activated 
    macrophages) 在纤维化的免疫耐受开展了大量工作。

5. 发表的文章:
     
     Peer-Reviewed
     1. Yuan-Ping Han, Kohanski RA. “Phenylarsine oxide inhibits insulin activation of phosphatidylinositol 
     3'-kinase”.  
     Biochem Biophys Res Commun 1997 Oct 9;239 (1):316-21.

     2.   Frankel M, Bishop SM, Ablooglu AJ, Yuan-Ping Han, Kohanski RA. “Conformational changes in the 
     activation loop of the insulin receptor's kinase domain”. 
     Protein Science 1999 Oct; 8(10): 2158-65.   

     3.   Yuan-Ping Han, Tuan TL, Wu H, Hughes M, Garner WL, “TNF-alpha stimulates activation of pro-MMP2 in 
     human skin through NF-kappa B mediated induction of MT1-MMP”. 
     Journal of Cell Science 2001; 114(Pt 1):131-139.

     4.  Yuan-Ping Han, Tai-Lan Tuan, Huayang Wu, Michael Hughes, Warren L. Garner.  “TGF-beta and TNF-alpha 
     mediated induction and proteolytic activation of MMP-9 in human skin”. 
     Journal of Biological Chemistry. 2001, vol.276 (25); 22341-22350.
     
     5.  Yuan-Ping Han, Micheal W. Hughes, Yih-Dar Nien and Warren L. Garner. 
     “IL-8-Stimulated Expression of Urokinase-Type Plasminogen Activator in Human Skin and Human Epidermal 
     Cells”. 
     Journal of Surgery Research. 2002 Aug;106(2):328.
     
     6.  Mei Chen, Fritz K. Costa, Christopher R. Lindvay, Yuan-Ping Han, and David T. 
     Woodley. “The Recombinant Expression of Full-length Type VII Collagen and   
     Characterization of Molecular Mechanisms Underlying Dystrophic Epidermolysis 
     Bullosa”.  
     Journal of Biological Chemistry. 2002, vol. 277: 2118-2124.
     
     7.   Yuan-Ping Han, Yih-Dar Nien and Warren L.Garner. “Recombinant human platelet-derived growth factor 
     and transforming growth factor-beta mediated contraction of human dermal fibroblast populated lattices 
     is inhibited by Rho/GTPase inhibitor but not require phosphatidylinositol-3’ kinase”. 
     Wound Repair and Regeneration. 2002, vol. 10, 169-176.                    
          
     8.   Yuan-Ping Han*, Yih-Dar Nien and Warren L.Garner. “TNF-alpha  mediated proteolytic activation of 
     pro-MMP-9  in human skin is controlled by down regulation of the tissue inhibitor, TIMP-1 and mediated 
     by tissue bound chymotrypsin-like proteinase”. 
     Journal of Biological Chemistry. 2002, 277:   27319-27327.
     
     9.  Yuan-Ping Han, Yih-Dar Nien and Warren L.Garner. “Fibrinogen inhibits fibroblast-mediated 
     contraction of collagen”. 
     Wound Repair and Regeneration. 2003 Sep;11(5):380-385.
     
     10.  Yuan-Ping Han*, Ling Zhou, Jiaohong Wang, Shigang Xiong, Warren L. Garner, Samuel W. French, 
     Hidekazu Tsukamoto.  “Essential role of matrix metalloproteinases in interleukin-1 induced 
     myofibrobalstic activation of hepatic stellate cell in collagen”. 
     Journal of Biological Chemistry.  2004, vol. 279, 4820-4828
     
     11. Yuan-Ping Han, Downey S and Warren L.Garner. “Interleukin-1alpha-induced proteolytic activation of 
     metalloproteinase-9 by human skin”.  
     Surgery. 2005 Nov;138(5):932-9.
     
     12. Yuan-Ping Han*. “Matrix metalloproteinases, the pros and cons, in liver fibrosis”. 
     Journal of Gastroenterology & Hepatology. 2006 Oct; 21 Suppl 3:S88-91.
     
     13. Yuan-Ping Han*, Chunli Yan, Ling Zhou, Lan Qin, and Hidekazu Tsukamoto. “A Matrix 
     Metalloproteinase-9 Activation Cascade by Hepatic Stellate Cells in Trans-differentiation in the hree-
     dimensional Extracellular Matrix”. 
     Journal of Biological Chemistry.  2007 Apr 27;282(17):12928-39
      
     14.  Goldberg MT, Han YP, Yan C, Shaw MC, Garner WL. “TNF-alpha Suppresses alpha-Smooth Muscle Actin 
     Expression in Human Dermal Fibroblasts: An Implication for Abnormal Wound Healing”. 
     Journal of Investigative Dermatology. 2007 May 31;127 (11):2645-55
      
     15.	Cheng JH, She H, Han YP, Wang J, Xiong S, Asahina K, Tsukamoto H. “Wnt 
     antagonism inhibits hepatic stellate cell activation and liver fibrosis”. 
     American Journal of  Physiololy, (Gastrointest Liver Physiol) 2007, Nov 15; [Epub ahead of print] PMID: 
     18006602 
     
     16.  Yuan-Ping Han*, Chunli Yan and Warren L Garner. “Proteolytic Activation of Matrix 
     Metalloproteinase-9 in Skin Wound Healing Is Inhibited by alpha-1-Antichymotrypsin”.
     Journal of Investigative Dermatology. 2008 September; 128(9): 2334–2342.
     
     17.  Chunli Yan, Ling Zhou, and Yuan-Ping Han*. “Contribution of hepatic stellate cells and matrix 
     metalloproteinase-9 in acute liver failure”.  Liver International. 2008 May 26. [Epub ahead of print].
     
     18.  Cheng CF, Fan J, Fedesco M, Guan S, Li Y, Bandyopadhyay B, Birght AM, Yerushalmi D, Liang M, Chen, 
     Han YP, Woodley DT, Li W.  “Transforming growth factor alpha (TGFalpha)-stimulated secretion of 
     HSP90alpha: using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFbeta-rich 
     environment during wound healing”.  
     Molecular Cell Biolology. 2008 May;28(10):3344-58. Epub 2008 Mar 10, MID:18332123.
     
     19. Ling Zhou, Chunli Yan, Wei Li, Yujiro Kida, Warren L. Garner and Yuan-Ping Han*. “p21 activated 
     kinase (PAK) controls expression of MMP-9”. 
     BMC Immunology 2009, 10:15,19 March
     
     20. Roben L. Gieling, Wallace, K. and Yuan-Ping Han*, “Participation of Interleukin-1 in Liver Injury 
     induced Fibrosis”. 
     American Journal of Physiology, (Gastrointest Liver Physiol) . 2009, vol. 296,1324-31
     
     21. MJ Reiss, Yuan-Ping Han, E Garcia, YK Hong, and WL Garner “1-Antichymotrypsin activity correlates 
     with and may modulate matrix metalloproteinase-9 in human acute wounds ”. 
     Wound Healing and Regeneration, 2009, Published Online: May 20 2009, p 418-426
     
     22.  Shengwen Calvin Li, Yuan-Ping Han, Brent A. Dethlefs and William Gunter Loudon “Therapeutic Window 
     of Stem Cell Potential for Targeting Pediatric Malignant Brain Tumor: An Opportunity for Stem Cell 
     Therapy”. 
     Stem Cell Review and Reports, 2009, vol.5, issue 4, p446
     
     23. MJ Reiss, Yuan-Ping Han, E Garcia, YK Hong, and WL Garner “Excessive Amount of Matrix 
     Metalloproteinase-9 Delays Wound Healing in a Murine Wound Model”. 
     Surgery, 2010, February, Volume 147, Issue 2, Pages 295-302
     
     24. Keigo Machida, Hidekazu Tsukamoto, Jian-Chang Liu, Yuan-Ping Han, Sugantha Govindarajan, Michael 
     Lai, Shizuo Akira, James Ou, “c-Jun mediates HCV hepatocarcinogenesis through STAT3 and nitric oxide-
     dependent impairment of oxidative DNA repair”. 
     Hepatology, 2010 Aug;52(2):480-92 
     
     25. Chunli Yang, Wesley Grimm, Warren Garner, and Yuan-Ping Han*, “Tumor necrosis factor-alpha induced 
     epithelial-to-mesencymal transition in human skin fibrogenesis is mediated by bone morphogenetin 
     protein-2”. 
     American Journal of Pathology, 2010, May. 176: 2247-2258. (Cover story)
     
     26. Lan Qin and Yuan-Ping Han*. “Epigenetic Repression of Matrix Metalloproteinases in Myofibroblastic 
     Hepatic Stellate Cells through Histone Deacetylases 4,Implication in Tissue Fibrosis ”.  
     American Journal of Pathology, 2010, volume 177, Issue 4, page 1915 (Monthly Highlight)
     
     27. Xiaohui Zhou, Zanxian Xia, Qin Lan, Julie Wang, Wenru Su,Yuan-Ping Han, Huimin Fan, Zhongmin 
     Liu, William Stohl, and Song Guo Zheng. “BAFF Promotes Th17 Cells  and Aggravates Experimental 
     Autoimmune Encephalomyelitis”. 
     PloS One, 2011; 6(8): Published online 2011 August. doi:  10.1371, PMCID: PMC3163640
     
     
     28. Yujiro Kida, Zan Xian Xia, Sujun Zheng, Nick M. Mordwinkin, Stan G. Louie, Song Guo      Zheng, Min 
     Feng, Hongbo Shi, Zhongping Duan, and Yuan-Ping Han*. “Interleukin-1 as an  injury signal mobilizes 
     retinyl esters in hepatic stellate cells through down regulation of lecithin retinol acyltransferase”.  
     PLoS One, 2011. 6(11): e26644. doi:10.1371/journal.pone.0026644
     
     29. Ling Lu, Jilin Ma, Zhiyuan Li, Qin Lan, Maogen Chen, Ya Liu, Zanxian Xia, Julie Wang, Yuan-Ping Han, 
     Wei Shi, Valerie Quesniaux, Bernhard Ryffel, David Brand, Bin Li, Zhongmin Liu, Song Guo Zheng. “All-
     Trans Retinoic Acid Promotes TGF-β-Induced Tregs via Histone Modification but Not DNA Demethylation on 
     Foxp3 Gene Locus”.
     PloS One, 2011; 6(9): e24590. doi:10.1371/journal.pone.0024590. 
     
     30. Liyan Chen, Feng Ren, Haiyan Zhang, Tao Wen, Zhengfu Piao, Li Zhou, Sujun Zheng,    Jing Zhang, Yu 
     Chen, Yuanping Han, Zhongping Duan, Yingji Ma. “Inhibition of  Glycogen Synthase Kinase 3b Ameliorates D-
     GalN/LPS-Induced Liver Injury by   
     Reducing Endoplasmic Reticulum Stress-Triggered Apoptosis” 
     PLoS One, 2011. September 2012 | Volume 7 | Issue 9 | e45202
     
     31. Ling Lu, Jilin Ma, Zhiyuan Li, Qin Lan, Maogen Chen, Ya Liu, Zanxian Xia, Julie   
     Wang, Yuanping Han, Wei Shi, Valerie Quesniaux, Bernhard Ryffel, David    
     Brand, Bin Li, Zhongmin Liu, and Song Guo Zheng “All-Trans Retinoic Acid Promotes 
     TGF-β-Induced Tregs via Histone Modification but Not DNA Demethylation on Foxp3  Gene Locus”. 
     PLoS One. 2011; 6(9): e24590.Published online 2011 
     
     32. Yuan-Ping Han*, Ming Kong, Sujun Zheng, Yang Ren, Hongbo Shi, and Zhongping Duan.  
      “Vitamin D In Liver Diseases: From Mechanisms to Clinical Trials”. 
     Journal of Gastroenterology and Hepatology. 2013; 28, Suppl.1: 49–55
      
     33. Ling Lu, Min Feng, Lan Qin et al., Yuan-Ping Han*. “Induction of hepatic regulatory T cells is 
     mediated by MMP13 dependent activation of latent TGF-beta by hepatic stellate cells”.  
     Journal of Molecular Cell Biology, 2013, December Issue, in press