基因转移和基因治疗研究室

　　我们应用分子生物、细胞生物及基因改造动物模型，并收集临床有关病例和家系，开展了从基础到临床对严重高脂血症的研究。在国内外以高胆固醇为主要研究方向的形势下，我们扬长避短，根据自己的优势和中国人高甘油三酯血症发病率高的特点，以多学科（心血管、消化、神经、纳米技术）的国内外合作为基础，开展了具有特色的严重高甘油三酯血症的研究项目，发表了一系列的研究论文，获得了2007年北京国际心血管病论坛“有影响的心血管论文奖”、2006年北京大学医学部“优秀SCI论文”和基础医学院“走向世界优秀论文”等奖励。

　　具体的研究方向包括：

　　一、严重高甘油三酯血症及其所致多器官损害的机制研究

　　1. 严重高甘油三酯血症的自发性动脉粥样硬化及其机理：

　　2. 严重高甘油三酯血症导致的急性胰腺炎及其机理：

　　3．原发性LPL缺陷和严重高甘油三酯血症的中枢神经系统损伤及其机理：

　　4．糖尿病与严重高甘油三酯血症的关系研究

　　5．高甘油三酯血症的血液流变学异常及血凝障碍

　　6．高甘油三酯血症与肾脏损伤关系的研究

　　二、其它相关研究方向：

　　1．利用泡沫细胞模型和联合性高胆固醇/高甘油三酯小鼠开展的降脂药物筛选。

　　2．树枝状纳米粒子基因载体的研究。

　　3．高脂血症的大动物模型研究。

　　4．微流芯片技术在脂蛋白代谢研究中的应用。

　　Research Description:

　　The research of our laboratory focuses on severe dyslipidemia and related diseases. Dyslipidemia has been one of the most prevailing diseases in recent years in China. According to the newly released online data by the Ministry of Health, nearly 160 million Chineses suffer from dyslipidemia currently. As it is in the western countries, atherosclerotic vascular diseases associated with dyslipidemia, exceeding malignant tumors, have become the No.1 killer in China.

　　We developed research programs on severe hypertriglyceridemia, one of the most common forms in dyslipidemia, by basic and clinical approaches.， including：mechanisms of severe hypertriglyceridemia induced multiple organ injury; development of gene-modified large animal models with hyperlipidemia, application of microfluidic chip in lipoprotein metabolism.

　　承担的科研项目：

　　一．国家自然科学基金项目:

　　1. 创新群体项目子课题: 代谢综合症及其血管病变的研究：严重高甘油三酯血症的发生机理及防治。项目负责人：王宪，子课题负责人：刘国庆。

　　2.重点项目：高甘油三酯血症引起多器官功能改变的氧化应激损伤机理研究。负责人：刘国庆。

　　3. 面上项目：脂肪缺失的Seipin基因敲除小鼠高甘油三酯血症和动脉粥样硬化的发生机制。负责人：刘国庆。

　　4. 面上项目：聚乙二醇化树状高分子载体构建纳米给药系统促进普罗布考口服相关疗效及机理研究。负责人：祁荣。

　　5. 面上项目：脂蛋白脂酶基因缺陷对糖尿病性动脉粥样硬化和晚期肾损伤的影响及其机制研究。负责人：黄薇。

　　6. 面上项目：聚乙二醇修饰的树状分子聚合物纳米基因载体在单基因缺陷所致的高脂血症的基因治疗研究中的应用。负责人：祁荣。

　　7. 面上项目：应用脂肪特异性转基因/基因敲除小鼠模型对Seipin功能的研究。负责人：王宇辉。

　　8. 面上项目：应用SRB1和LPL基因缺陷小鼠研究ApoAV 降低甘油三酯的机理。负责人：刘国庆。

　　9. 面上项目：小鼠脂蛋白脂酶基因缺陷在I型糖尿病肾病中的作用及其机制研究。负责人：黄薇

　　10. 面上项目：树枝状纳米材料作为非病毒基因载体在高脂血症及动脉粥样硬化基础研究中的应用。负责人：祁荣。

　　11. 面上项目：遗传性ACE基因表达水平的改变对小鼠II型糖尿病肾病不同时期的影响。负责人：黄薇。

　　二．教育部项目：

　　博导类基金（刘国庆）。

　　教育部留学归国人员启动基金4项（刘国庆，黄薇，王宇辉，祁荣）。

　　三．科技部项目：

　　1．863计划：以RNA干扰技术建立遗传性脂代谢相关基因敲下家兔模型的关键技术研究（已结题）

　　2．973计划子项目：代谢性血管病研究：糖尿病合并高脂血症的器官损害研究

　　3. 973计划：动脉粥样硬化发病机制及其诊治与干预的基础研究：脂代谢紊乱导致动脉粥样硬化发病的分子机制。子课题负责人：刘国庆。

　　4. 973计划：脂肪肝和高脂血症的分子机制。子课题骨干：刘国庆。

　　5. 973计划：纳米技术改善难溶性药物功效的应用基础研究：纳米剂型跨膜转运机制研究。子课题骨干：祁荣。

　　四. 北京市自然科学基金重点项目

　　心血管疾病基因修饰家兔模型的关键技术研究。负责人：刘国庆。

　　五．国际合作项目：

　　1．脂蛋白脂酶的多功能作用－对动脉硬化和脑功能的影响研究（由加拿大CIHR和国家自然科学基金委资助）

　　2．脂蛋白亚组分微流芯片分析技术研究（由美国Agilent公司分子诊断部资助）

　　3. 海外及港澳学者合作研究基金：Seipin在肝脏脂质代谢中的作用。负责人：刘国庆。

　　4. PLC对LDL－R基因缺陷糖尿病小鼠动脉粥样硬化的治疗作用研究，日本大冢制药厂资助。负责人：刘国庆。

　　研究室成员

　　刘国庆，男，教授，博士生导师。

　　黄薇，女，副教授，硕士生导师。

　　王宇辉，男，副研究员。

　　祁荣，女，副教授。

　　张玲，女，主管技师

　　Selected Publications ：

　　1. Jiang M, Gao M, Wu C, He H, Guo X, Zhou Z, Yang H,Xiao X, Liu G* and Sha J. Lack of testicular seipin causes teratozoospermia syndrome in men. PNAS. 2014, 111(19):7054-9

　　2. Zhou L, Yin J, Wang C, Liao J, Liu G* and Chen L. Lack of seipin in neurons results in anxiety- and depression-like behaviors via down regulation of PPARγ. Hum Mol. Gen.March. 2014，24(3):380-2

　　3. Bi B, Wang W, Liu Z, Huang X, Jiang Q, Liu G, Wang Y and Huang X: Seipin promotes adipose tissue fat storage through the ER Ca2+-ATPase SERCA. Cell Metabolism 2014,19(5):861-71

　　4. Wang Y, Chiu A, Neumaier K, Wang F, Zhang D,Bahira H, Lal N, Wan A, Liu G, Vlodavsky I and Rodrigues B: Endothelial Cell Heparanase Taken Up by Cardiomyocytes Regulates Lipoprotein Lipase Transfer to the Coronary Lumen following Diabetes, Diabetes, March, 2014, Epub ahead of print

　　5. Liu L, Jiang Q, Zhang B, Wang Y, Cui X, Gao M, Lv Y, Xu G, Zhao D, Liu G* and Yang H. Adipose-specific knockout of seipin/BSCL2 results in progressive lipodystrophy. Diabetes. 2014, 63(7):2320-31

　　6. Gao M, Zhang B, Liu. J, Guo X, Li H, Wang T, Zhang Z, Liao J, Cong N, Wang Y, Yu L, Zhao D and Liu G*: Generation of transgenic golden Syrian Hamsters. Cell Research,2014, 24:380-382

　　7. Guo F, Ma Y, Kadegowda AK, Xie P, Liu G, Liu X, Miao H, Ou J, Su X, Zheng Z, Xue B, Shi H, Yu L：Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice.J Lipid Res, 2013,54(8):2109-20

　　8. Tang Y, LiYB, WangB, LinRY, van Don}en M, ZurcherDM,GuXY,Banaszak-Holl MM, LiuGQ*,QiR*. Efficient in Vitro siRNA Delivery and Intramuscular Gene Silencing Using PEG-Modified PAMAM Dendrimers. Mol Pharm, 2012, 9: 1812-1821. (SCI，IF="5.4)

　　9. Cui X, Wang Y, Meng L, Deng J, Xu G, Peng X, Ju S, Teng G, Liu G*, Zhao L and Yang H: Overexpression of a short human seipin/BSCL2 isoform in mouse adipose tissue results in mild lipodystrophy. Am. J. Physiol. Endocrinology and Metabolsim Jan. 2012, Epub ahead of print. (IF ="4.8)"

　　10. Ding Y, Zhang L, Wang Y, Huang W, Tang Y, Bai L, Ross CJR, Hayden MR, G Liu*: Amelioration of Hypertriglyceridemia with Hypo-alpha-cholesterolemia in LPL Deficient Mice by Hematopoietic Cell-Derived LPL. PLos One. 2011, 6(9):e25620.(IF ="4.5)"

　　11. Wei J, Ouyang H, Wang Y, Pang D, Cong XN, Wang T, Leng B, Li D, Li X, Wu R, Gao F, Deng Y, Liu B, Li Z, Lai L, Feng H, Liu G*, Deng X: Characterization of A Hypertriglyceridemic Transgenic Miniature swine Model expressing Human Apolipoprotein CIII. FEBS J 2011 Oct.Epub ahead of print.(IF ="2.7)

　　12. Hu G, Zhao Y, Tang Y, Wang Y, Liu L, Li H, Liu Y, Cui X, Yu Y, Guo C, Wang X, Liu G*: Development of A Novel Model of Hypertriglyceridemic Acute Pancreatitis in Hamster: Protective Effects of Probucol. Pancreas Oct. 2011, Accepted. (IF ="2.4)"

　　13. Peng X, Ju S, Qin Y, Fang F, Cui X, Liu G, Ni Y, Teng G: Quantification of Liver Fat in Mice: Comparing Dual-Echo Dixon Imaging, Chemical Shift Imaging and 1H-MR Spectroscopy. J Lipid Res.2011, Epub ahead of print. (IF ="6.2)

　　14. Cui X, Wang Y, Tang Y, Liu Y, Zhao L, Deng J, Xu G, Peng X, Ju S, Liu G* and Yang H: Seipin ablation in mice results in severe generalized lipodystrophy. Human Molecular Genetics 2011,20(15):3022-30.(IF ="8.1)

　　15. Wang Y, Tong J, Li S, Zhang R, Chen L, Zheng M, Wang M, Wang Y, Liu G, Dai D, Zhao Y, Li N: Over-expression of Human Lipoprotein Lipase in Mouse Mammary Glands Leads to Reduction of Milk Triglyceride and Delayed Growth of Suckling Pups. PLos One May, 2011, Epub ahead of print. (IF ="4.5)

　　16. Ding Y, Wang Y, Zhu H, Fan J, Yu L, Liu G* and Liu E: Hypertriglyceridemia and delayed clearance of fat load in transgenic rabbits expressing human apolipoprotein CIII. Transgenic Research. 2011，20(4):867-75. (IF ="2.4)

　　17. Dong LH, Wen JK, Liu G, McNutt MA, Miao SB, Gao R, Zheng B, Zhang H, Han M：Blockade of the Ras-extracellular signal-regulated kinase 1/2 pathway is involved in smooth muscle 22 alpha-mediated suppression of vascular smooth muscle cell proliferation and neointima hyperplasia.ArteriosclerThrombVasc Biol.2010; 30(4):683-91. (IF ="7.2)

　　18. Jia L, Ma Y, Liu G, Yu L. Dietary cholesterol reverses resistance to diet-induced weight gain in mice lacking Niemann-Pick C1-Like 1. J Lipid Res.2010; 51(10):3024-33.(IF ="6.2)"

　　19. Gao S, He L, Ding Y and Liu G*: Mechanisms underlying different responses of plasma triglyceride to high-fat diets in hamsters and mice: Roles of hepatic MTP and triglyceride secretion. BBRC 2010;398(4):619-26. (IF ="2.4)

　　20. Ding Y, Wang Y, Huang W, Liu G, Ross C, Hayden MR, Yang J: Glucose intolerance and decreased early insulin response in mice with severe hypertriglyceridemia. Exp.Biol.Med. 2010，235:40-46.(IF ="2.8)"

　　21. Rong Qi, Douglas G. Mullen, James R. Baker, Jr., Mark M. BanaszakHoll. The Mechanism of Polyplexes Internalization into Cells: Testing the GM1/Caveolin-1 Lipid Raft Mediated Endocytosis Pathway. Mol Pharm, 2010, 7(1):267-79. (SCI，IF="4.6)

　　22. Xian X, Ma Y, Yang DD, Huang W, Wang Y, Mueller O, Chang E; Konigshofer Y; Van-Cleve M, Yang J and Liu G: Reduced HDL2b in non-obese type 2 diabetic patients analyzed by a microfluidic chip method in a case-control study. Biomarkers.Accepted, July. 2009. (IF ="2.2)

　　23. Ma Y, Zhao L, Xian X, Yang D; Huang W, Wang Y, Mueller O, Chang E, Konigshofer Y, Van-Cleve M, Liu G, Yang J. A case-control study on the relationship between the HDL2b and nonacoholic fatty liver disease in Chinese type 2 diabetic patients. ClinChem Lab Med.Accepted, July 2009. (IF ="1.8)

　　24. Xian X, Ding Y, Zhang L, Wang Y, McNutt M, Ross C, Hayden M, Deng X, Liu G: LPL deficiency promotes neointimal formation after oxidative arterial wall injury in ApoE-deficient mice. BBRC.2009，385(4):563-9. (IF ="2.9)

　　25. Qi R, Gao Y, Liu T, He R, Tang Y, He Y, Sun S, Li B, Li Y and Liu G: PEG-conjugated PAMAM dendrimers mediate efficient intramuscular gene expression. AAPS J.2009, 11(3): 395-405. (SCI，IF="5.5)

　　26. Zheng J, Tang L, Xian X, Zhou S, Shi H, Jiang Y, Gu Y, Liu G and Tu P: Inhibitory Effect of TriterpenoidSaponins from the Leaves of Ilex kudingcha on Aggregated LDL-Induced Lipid Deposition in Macrophages. Planta Med.Epub ahead of print, May, 2009. (IF ="1.2)

　　27. Xian X, Liu T, Yu J, Wang Y, Miao Y, Zhang J, Yu Y, Ross C, Karasinska J, Hayden M, Liu G, Chui D: Presynaptic Defects underlying Impaired Learning and Memory Function in Lipoprotein Lipase Deficient Mice. J. Neuroscience.2009，29(14):4681-5. (IF ="7.5)

　　28. Yang F, Wang Y, Sternfeld L, Rodriguez JA, Ross C, Hayden MR, Carriere F, Liu G and Schulz I: The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiol.2009,195:13-28. (IF ="2.3)"

　　29. Wang Y, Sternfeld L, Yang F, Rodriguez JA, Ross C, Hayden MR, Carriere F, Liu G, Hofer W and Schulz I: Enhanced susceptibility to pancreatitis in severe hypertriglyceridemic lipoprotein lipase deficient mice and agonist-like function of pancreatic lipase in pancreatic cells. Gut.2009; 58(3):422-30.(IF ="10.2)"

　　30. Ebara T, Murase T, Okubo M, Hayden M and Liu G: Is LPL deficiency atherogenic? Circulation Research.2008;102(11):e118-e119. (IF ="9.8)

　　31. Zhang X, Qi R, Xian X, Yang F, Blackstein M, Deng X, Fan J, Ross C, Hayden MR, Liu G: Spontaneous atherosclerosis in aged LPL deficient mice with severe hypertriglyceridemia on a normal chow diet. Circulation Research.2008; 102(2):250-6.(IF ="9.8)

　　32. GaoY, GaoG, HeY, LiuTL, QiR*. Recent Advances of Dendrimers in Delivery of Genes & Drugs. Mini Reviews in Medicinal Chemistry, 2008, 8(9): 889-900. (SCI，IF="3.2)

　　33. Wang J, Xian X, Huang W, Chen L; Wu L; Zhu Y, Fan J, Ross C, Hayden MR, Liu G: Rapid Lipid Deposition and VCAM-1 Up-Regulation in Endothelial-Intact Carotid Artery via Arterial Expression of Lipoprotein Lipase in Both Lipoprotein Lipase and Apolipoprotein E Deficient Mice. Arterio.Thromb.Vasc.Biol 2007 27(1):197-203. (IF ="7.1)."

　　34. Huang W, Bi N, Zhang X, Wang Y, Chen B, Liu G. Overexpression of apolipoprotein AV in the liver reduces plasma triglyceride and cholesterol but not HDL in ApoE deficient mice. BBRC. 346:14-18, 2006. (IF ="3.0)"

　　35. Zhao T, Guo J, Ross C, Hayden MR, Wen Z, Liu G Hemorheologic abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia. BBRC, 341:1066-71, 2006. (IF ="3.0)"

　　36. Yu X,, Zhao T, Wang L, Liu Z, Zhang C, Chen R, Li L, Liu G, Hu W: A novel substitution at the translation initiator codon (ATG . ATC) of the lipoprotein lipase gene is mainly responsible for lipoprotein lipase deficiency in a patient with severe hypertriglyceridemia and recurrent pancreatitis. BBRC 341:82–87, 2006. (IF ="3.0)"

　　37. Wu X, Wang J, Fan J, Chen M, Chen L, Huang W, Liu G：Localized vessel expression of lipoprotein lipase in rabbits leads to rapid lipid deposition in the balloon-injured arterial wall. Atherosclerosis. 187：65-73，2006. (IF ="3.7)"

　　38. Ross CJ, Liu G, Kuivenhoven JA, Twisk J, Rip J, van Dop W, AshbourneExcoffon KJ, Lewis SM, Kastelein JJ, Hayden MR. Complete Rescue of Lipoprotein Lipase-Deficient Mice by Somatic Gene Transfer of the Naturally Occurring LPLS447X Beneficial Mutation. ArteriosclerThrombVasc Biol. 25: 2143-50, 2005, with editorial comments 25:2018-9. (IF ="7.1)"

　　39. Koike T, Liang J, Wang X, Ichikawa T, Shiomi M, Sun H, Watanabe T, Liu G, Fan J. Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase.Cardiovasc Res. 65:524-3, 2005. (IF ="5.2)"

　　40. Zhang A, Gao S, Fan J, Huang W, Zhao T, and Liu G.: Increased plasma HDL cholesterol levels and biliary cholesterol excretion in Hamster by LCAT overexpression.FEBS Letter 570:25-9，2004. (IF ="3.6)"

　　41. C J.D. Ross, J Twisk, J. M. Meulenberg, G Liu, K. Van Den Oever, E Moraal, W. Hermens, J Rip, J. J.P. Kastelein, Jan A Kuivenhoven, and M. R. Hayden: Long-term correction of murine lipoprotein lipase deficiency with AAV1-mediated gene transfer of the naturally occurring LPLS447X beneficial mutation. Human Gene Therapy 15:906–919, 2004. (IF ="5.0)"

　　42. Koike T, Liang J, Wang X, Ichikawa T, Shiomi M, Liu G, Sun H, Watanabe T, Yamada N, Fan J.：Overexpression of lipoprotein lipase in transgenic WHHL rabbits improves hyperlipidemia and obesity. J BiolChem 279:7521, 2004. (IF ="6.5)."

　　43. Singaraja RR, Bocher V, James ER, Clee SM, Zhang LH, Leavitt BR, Tan B, Brooks-Wilson A, Kwok A, Bissada N, Yang YZ, Liu G, Tafuri SR, Fievet C, Wellington CL, Staels B, Hayden MR. Human ABCA1 BAC transgenic mice show increased high density lipoprotein cholesterol and ApoAI-dependent efflux stimulated by an internal promoter containing liver X receptor response elements in intron 1. J BiolChem 2001，276(36):33969-79. (IF ="6.5)"

　　44. Kastelein JJ, Jukema JW, Zwinderman AH, Clee S, van Boven AJ, Jansen H, Rabelink TJ, Peters RJ, Lie KI, Liu G, Bruschke AV, Hayden MR. Lipoprotein lipase activity is associated with severity of angina pectoris. REGRESS Study Group. Circulation 2000，102(14):1629-33.（IF＝11）

　　45. G. Liu,K.J.D.Ashborn-Excoffon,J.E. Wilson, B. M. McManus, L. Miao, S.M.E.Lewis and M.R.Hayden : Phenotypic Correction of feline lipoprotein lipase (LPL) deficiency by adenoviral gene transfer.Human Gene Therapy 11:21-33,2000. (IF ="5.0)

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