脂代谢紊乱与代谢性血管疾病实验室
PI-冼勋德
实验室介绍
心脑血管疾病是目前影响人类健康的第一杀手，其中以脂代谢紊乱所致的血管动脉粥样硬化是其主要因素。因此，利用动物模型模拟人类疾病来研究脂代谢异常与血管性疾病成为关键。鉴于现在全球科研人员越来越认识到小鼠疾病和人类疾病的区别，研发和构建人源化、类人化动物模型开展转化医学研究，是未来生物医学领域发展的主攻方向和热点。冼勋德领导的课题组长期从事脂代谢紊乱与代谢性疾病的研究，并率先在世界范围内创建了基因工程仓鼠技术平台，建立了一系列拥有我国自主知识产权的脂代谢紊乱的基因工程仓鼠模型，如LDLR、ApoC2、LCAT、ApoC3、IL-10、ABCA1、IDOL等基因敲除仓鼠，系统阐明了利用拟人化仓鼠模型研究脂代谢紊乱与动脉粥样硬化的优势，并在国际高水平杂志Circulation Research、Arteriosclerosis，Thrombosis，and Vascular Biology、EBioMedicine、Metabolism、eLife、PNAS等发表了一系列代表性论文，获得以加拿大著名脂代谢专家Khosrow Adeli和美国科学院院士Peter Tontonoz教授等国外专家的高度认可。同时课题组还与国内外多家大型制药公司（诺和诺德，诺华等）深入合作，进行新药开发的临床前研究，已有相关成果发表。目前课题组与北京五加和生物技术有限公司建立了长期的合作伙伴关系，利用新一代AAV介导的基因修饰技术来创建新型基因修饰仓鼠模型和基因治疗技术。
研究方向：脂代谢紊乱导致心血管系统、神经系统、消化系统等疾病的病理机制研究。
基金情况：
国家自然科学基金(NSFC)：四项，经费330万；
北京大学专项经费：一项，200万；
北京大学医学-X项目：两项，经费20万。
工作人员：Co-PI黄薇、王宇辉副研究员；张玲主管技师。
在读研究生情况：
郭家宝、赖平平；师浩哲、郜凤英；李靖谊、周子豪、刘长允、韩雨非；马平、陈功烈。
主要发表论文情况：
1. Shi H*, Guo J*, Yu Q, Hou X, Liu L, Gao M, Wei L, Zhang L, Huang W, Wang Y, Liu G, Tontonoz P, Xian X# (corresponding author). CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis. Front Immunology. 2022. Accepted (IF=8.786).
2. Xu Y*, Guo J*, Zhang L*, Miao G, Lai P, Zhang W, Liu L, Hou X, Wang Y, Huang W, Liu G, Gao M#, Xian X# (corresponding author). Targeting ApoC3 Paradoxically Aggravates Atherosclerosis in Hamsters With Severe Refractory Hypercholesterolemia. Front. Cardiovasc. Med., 02 February 2022 | https://doi.org/10.3389/fcvm.2022.840358.(IF=5.847)
3. Liang C, Wang X, Peng K, Lai P, Liu Z, Ma J, Chen X, Liu G, Zheng M, Wang Y, Yang H, Liu G, Xian X#（corresponding author）, Gao M#. Idol Depletion Protects against Spontaneous Atherosclerosis in a Hamster Model of Familial Hypercholesterolemia. Oxid Med Cell Longev. 2022 May 24;2022:1889632. doi: 10.1155/2022/1889632. eCollection 2022.(IF=7.31)
4. Xian X*(First author), Wang Y, Liu G. Genetically Engineered Hamster Models of Dyslipidemia and Atherosclerosis. Methods Mol Biol. 2022;2419:433-459. doi: 10.1007/978-1-0716-1924-7_26.
5. Pohlkamp T*, Xian, X* (co-first author), Wong C*, Durakoglugil M, Werthmann C, Saido, Evers B, White C, Connor J, Hammer R, Herz J. NHE6-Depletion Corrects ApoE4-Mediated Synaptic Impairments and Reduces Amyloid Plaque Load. eLife. 2021 (In press).(IF=8.713)
6. Guo M, Ma S, Xu Y, Huang W, Gao M, Wu X, Dong X, Wang Y, Liu G, Xian X#(corresponding author). Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters-Brief Report. Arterioscler Thromb Vasc Biol.2021. Jul;41(7):2141-2148.(IF=10.514)
7. Guo M, Liu Z, Xu Y, Ma P, Huang W, Gao M, Wang Y, Liu G, Xian X#(corresponding author). Spontaneous Atherosclerosis in Aged LCAT-Deficient Hamsters With Enhanced Oxidative Stress. Arterioscler Thromb Vasc Biol. 2020 Oct 1:ATVBAHA120315265. doi: 10.1161/ATVBAHA.120.315265. Online ahead of print. （IF:10.514）
8. Guo M, Xu Y, Dong Z, Zhou Z, Cong NX, Gao M, Huang W, Wang Y, Liu G, Xian X#(corresponding author). Inactivation of Apoc3 by CRISPR/Cas9 Protects Against Atherosclerosis in Hamsters. Circ Res. 2020 Nov 6;127(11):1456-1458. doi: 10.1161/CIRCRESAHA.120.317686. Epub 2020 Sep 21. （IF:23.123）
9. Yu Q, Ma X, Wang Y, Shi H, An J, Wang Y, Dong Z, Lu Y, Ge J, Liu G*, Xian X#(corresponding author), Sun A#. Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observational Cohort Study. Cardiovasc Drugs Ther. 2020 Aug 29. doi:10.1007/s10557-020-07060-3. Online ahead of print. （IF:4.069）
10. Chun Yang, Wenhong Tian, Sisi Ma, Mengmeng Guo, Xiao Lin, Fengying Gao, Xiaoyan Dong, Mingming Gao, Yuhui Wang, George Liu#, Xian X#(corresponding author). AAV-mediated ApoC2 gene therapy: reversal of severe hypertriglyceridemia and rescue of neonatal death in ApoC2 deficient hamsters. Molecular Therapy Methods & Clinical Developmemt. 2020 Jul 15;18:692-701. doi: 10.1016/j.omtm.2020.07.011. （IF:5.849）
11. Gao M, Yang C, Wang X, Guo M, Yang L, Gao S, Zhang X, Ruan G, Li X, Tian W, Lu G, Dong X, Ma S, Li W, Wang Y, Zhu H, He J, Yang H, Liu G#, Xian X#(corresponding author). ApoC2 Deficiency Elicits Severe Hypertriglyceridemia and Spontaneous Atherosclerosis: A Rodent Model Rescued From Neonatal Death. Metabolism: Clinical and Experimental. 2020 Jun 17;154296. doi:10.1016/j.metabol.2020.154296.1161/A（IF:6.159）TVBAHA.120.315265.
12. Lili Wei, Haozhe Shi, Xiao Lin, Xin Zhang, Yuhui Wang, George Liu#, Xian X#(corresponding author). Impact of Cholesterol on Ischemic Stroke in Different Human-Like Hamster Models: A New Animal Model for Ischemic Stroke Study. Cells. 2019 Sep; 8(9): 1028.
13. Jinjie Wang, Kunxiang He, Chun Yang, Xiao Lin, Xin Zhang, Yuhui Wang, George Liu#, Xian X#(corresponding author). Dietary Cholesterol Is Highly Associated with Severity of Hyperlipidemia and Atherosclerotic Lesions in Heterozygous LDLR-Deficient Hamsters. Int J Mol Sci. 2019 Jul 18;20(14). pii: E3515. doi: 10.3390/ijms20143515
14. Kunxiang He, Jinjie Wang, Haozhe Shi, Qiongyang Yu, Xin Zhang, Mengmeng Guo, Yuhui Wang, Xunde Xian#(corresponding author)and George Liu*. An interspecies study of lipid profile and atherosclerosis in familial hypercholesterolemia animal models with low density lipoprotein receptor deficiency. Am J Transl Res. 2019 May 15;11(5):3116-3127. eCollection 2019
15. Xunde Xian*#, Theresa Pohlkamp#, Murat S. Durakoglugil, Connie Wong, Jürgen K. Beck, Courtney Lane-Donovan, Joachim Herz*: Reversal of ApoE4 Induced Recycling Block as a Novel Prevention Approach for Alzheimer's Disease. eLife. 2018 Oct 30;7. pii: e40048. (Featured and Cover Article封面杂志)
16. Zhao Dong, Haozhe Shi, Mingming Zhao, Xin Zhang, Wei Huang, Yuhui Wang, Lemin Zheng, Xian X# (corresponding author)and George Liu#. Loss of LCAT Activity in the Golden Syrian Hamster Elicits Pro-atherogenic Dyslipidemia and Enhanced Atherosclerosis. Metabolism: Clinical and Experimental. 2018 Mar 8. pii: S0026-0495(18)30069-6.
17. Xin Guo, Mingming Gao, Yunan Wang, Xiao Lin, Liu Yang, Nathan Cong, Xiangbo An, Feng Wang, Kai Qu, Liqing Yu, Yuhui Wang, Jinjie Wang, Haibo Zhu, Xian X#(corresponding author) and George Liu#: LDL receptor gene targeted hamsters: a familial hypercholesterolemic rodent model with dominant inheritance characteristics. EBioMedicine 2018 Jan;27:214-224. doi: 10.1016/j.ebiom.2017.12.013 (期刊重点文章并受邀请加拿大脂代谢专家Dr Adeli撰写同刊评论An article with journal highlights and a commentary by Khosrow Adeli et al.).
18. Xunde Xian*#, Yinyuan Ding#, Marco Dieckmann*, Li Zhou, Mingxia Liu, John Parks, Robert E Hammer, Philippe Boucher, Shirling Tsai, Joachim Herz*: LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis. eLife 2017 Nov 16;6. pii: e29292. doi: 10.7554/eLife.29292
19. Yinyuan Ding#, Xunde Xian*#, William Holland, Shirling Tsai, Joachim Herz*: Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis. EbioMedicine. 2016;7:135-145. (期刊重点文章并受邀请美国脂代谢专家Dr Tontonoz撰写同刊评论An article with the accompanying commentary by Peter Tontonoz et al.)
20. Yinyuan Ding#, Linzhang Huang#, Xunde Xian#, Ivan S. Yuhanna, Catherine R. Wasser, Michael Frostcher, Chieko Mineo, Philip W. Shaul. Joachim Herz*: Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial adhesion and lesion macrophage accumulationd atherosclerosis. Science Signaling. 2016; 9(419):ra29.
21. Ying Chen#, Murat S. Durakoglugil#, Xunde Xian# and Joachim Herz*: ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proceeding of National Academy of Sciences. 2010;107(26):12011-62010;107(26):12011-6.
22. Xunde Xian#, Yahong Ma#, Danhui D. Yang, Wei Huang, Yuhui Wang, Odilo Mueller, Elain Chang, E, Yves Konigshofer, Mark Van-Cleve, Jinkui Yang*, George Liu*: Reduced high-density lipoprotein 2b in non-obese type 2 diabetic patients analyzed by a microfluidic chip method in a case-control study. Biomarkers. 2009; 14(8): 619–623. (IF=2.8)
23. Xunde Xian#, Yu Ding#, Ling Zhang, Yanan Wang, Michael A. McNutt, Colin Ross, Michael R. Hayden, Xuming Deng*, George Liu*: Enhanced atherothrombotic formation after oxidative injury by FeCl3 to the common carotid artery in severe combined hyperlipidemic mice. Biochemical and Biophysical Research Communications. 2009 May 28;385(4):563-569.
24. Xunde Xian#, Tingting Liu#, Jia Yu#, Yuhui Wang, Yifei Miao, Jianjun Zhang, Yan Yu,
Colin Ross, Hayden MR, George Liu*, and Dehua Chui*: Presynaptic Defects underlying Impaired Learning and Memory Function in Lipoprotein Lipase-Deficient Mice. Journal of Neuroscience. 2009 April 29(14):4681-4685.