资源描述
单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2020/10/18,*,Distinct phenotypes in severe hypertriglyceridemic mice:,spontaneous atherosclerosis, pancrearitis, impaired hemorheology and abnormal neuronal development,2020/10/18,1,Distinct phenotypes in severe,HyperTG in the world:,Meta, multi-variables, Epidemiological analysis:,HyperTG,is an independent risk factor of coronary artery disease,2020/10/18,2,HyperTG in the world:Meta,S447X,a naturally occurring C-terminal two amino acid truncation mutation,wild type LPL -KKSG,S447X LPL -KK,Incidence,: 18.8% of Caucasian, 25.4% Chinese, and 3% of Australian Aborigine,associated with:,Low TG, High HDL-C, Low CHD,Complete Rescue of Lipoprotein Lipase-Deficient Mice by Somatic Gene Transfer of the Naturally Occurring LPLS447X Beneficial Mutation.,Arterioscl. Thromb. Vasc. Biol. 2005 Jul 7,2020/10/18,3,S447X, a naturally occurring,% Survival rate of LPL-/- pups,Days after Birth,The Unique HyperTG Mouse Models,Adult LPL-/-mice,2020/10/18,4,% Survival rate of LPL-/- pups,TC TG,WT,58 5.8 7922.0,ApoE0,304 10.2* 14551.9 *,LPL0,189 58.0*3199773.2*,ApoE0/LPL0,817166.7*5988857.4*,Plasma Lipids Levels of KO Mice,2020/10/18,5,Plasma Lipids Levels of KO Mi,AAV-Mediated long term LPL gene therapy for murine extreme HTG,2020/10/18,6,AAV-Mediated long term LPL gen,2020/10/18,7,2020/10/187,LK-/- 15 m,WT 15 m,Lesion Quantitation,2020/10/18,8,LK-/- 15 mWT 15 mLesion,LK-/- 10m,WT 10m,LK+/- 10m,3 out of 8, 37,2020/10/18,9,LK-/- 10mWT 10mLK+/- 10m,WT,LK+/-,LK-/-,4m,15m,10m,Pending,2020/10/18,10,WTLK+/-LK-/-4m15m10mPending20,LK-/- 4m,WT 4m,LK+/- 4m,（40）,2020/10/18,11,LK-/- 4mWT 4mLK+/- 4m （4,Macrophage,WT 10M,Oil red O,LK+/- 15 m,LK-/- 15 m,（200）,2020/10/18,12,MacrophageWT 10MOil red OLK+,VCAM-1,VCAM-1,Oil red O,（200）,LK+/- 15 m,LK-/- 15 m,2020/10/18,13,VCAM-1VCAM-1Oil red O（200）L,4 month,10 month,15 month,WT,+/-,-/-,WT,WT,-/-,-/-,2020/10/18,14,4 month10 month15 monthWT+/-,CM oxidation,2020/10/18,15,CM oxidation2020/10/1815,15m,10m,4m,Oxidation of chylomicron by ESR analysis,2020/10/18,16,15m10m4mOxidation of chylomicr,RO production as reflected by,peak Height of ESR graph,4m,10m,15m,0,1,2,3,4,5,6,4 m,10 m,15 m,Product of RO,.,(cm/mg),2020/10/18,17,RO production as reflected by,Spontaneous atherosclerosis in hypertriglyceridemic murine model on normal chow diet,2020/10/18,18,Spontaneous atherosclerosis in,Alterations of Blood Coagulation,2020/10/18,19,Alterations of Blood Coagulati,Hemorheological changes in the mice,Hematocrit RBC Electroph. Rate,% of RBC Vol.,wt,E0,*,*,50.0,37.5,25.0,12.5,0,L0,E0/L0,1.00,0.75,0.50,0.25,0,Electrophoresis rate,2020/10/18,20,Hemorheological changes in t,Alterations of RBC Rheology,2020/10/18,21,Alterations of RBC Rheology202,Alterations in RBC polarization and microviscosity,Polarization Microviscosity,P value,of RBC ghost,wt,E0,*,*,0.20,0.15,0.10,0.05,0,L0,E0/L0,1.00,0.75,0.50,0.25,0,value of RBC ghost,*,*,*,*,2020/10/18,22,Alterations in RBC polarizat,Structural changes in RBC membrane as studied by FTIR:,2. Secondary structure of membrane protein,-turns -helix,-sheet -helix,A=1684 A=1659 A=1634 A=1545,Absorption value,wt,E0,*,*,2.00,1.50,1.00,0.50,0,L0,E0/L0,*,*,*,*,*,*,*,*,*,*,*,2020/10/18,23,Structural changes in RBC me,Hemorrheologic abnormalities in mice with severe hypertriglyceridemia and combined hypertriglyceridemia/cholesterolemia,2020/10/18,24,Hemorrheologic abnormalities i,Impact of extreme hypertriglyceridemia on atherogenesis: utilization of ApoE/ LPL double deficient mice,Aortic lesion development at 3, 6 and 9 month compared with ApoE0 and E0/LPL+/-mice;,Local expression of active and inactive hLPL in carotid arteries: identification of lipid deposition;,BMT as tool for evaluation of macrophage-specific deletion of LPL gene;,As model by FeCl injury on carotid artery for evaluation of the LPLs effect on atherogenesis,2020/10/18,25,Impact of extreme hypertriglyc,ApoE-/- XLPL-/- ApoE-/-,6 months,3 months,2020/10/18,26,ApoE-/- XLPL-/- ApoE,ELK -/-,EK -/-,ELK +/-,（40）,3 M,6 M,9 M,Pending,Pending,Pending,Pending,Pending,Pending,2020/10/18,27,ELK -/-EK -/-ELK +/-（40）3 M,External carotid artery,Common carotid artery,Internal carotid artery,Arterial wall gene transfer to mouse carotid artery,2020/10/18,28,External carotid arteryCommon,Local expression of active and inactive hLPL in carotid arteries in WT mice: RealTime quantitation of mRNA,1000 bp,500 bp,(-) AP WT 194 P M,1 2 3 4 5 6,-actin (500bp),400 bp,LPL (396 bp),AP LPL-WT LPL194,Ratio of LPL/ actin (X10,3,),1,2,2020/10/18,29,Local expression of active an,Ctl. LPL staining,LPL GT. LPL Staining,Ctl. ORO staining,LPL GT. ORO staining,Arterial expression of LPL gene in WT mice:,Promotion of Lipid Deposition,2020/10/18,30,Ctl. LPL stainingLPL GT. LPL,ORO staining,hAP hLPL,WT,hLPL,194,(200x),(400x),ApoE-/-,2020/10/18,31,ORO staininghAP,ORO staining,(200x),(400x),hAP,hLPL,WT,hLPL,194,LPL-/-,2020/10/18,32,ORO staining(200x)(400x) hAP,Ad-AP,Ad-LPLwt,Ad-LPL194,en face confocal microscopy images of VCAM-1 expression,LPL-/-,2020/10/18,33,Ad-APAd-LPLwtAd-LPL194en face,Rapid lipid deposition in endothelial-intact carotid artery via arterial expression of either active or inactive lipoprotein lipase in ApoE and LPL deficient mouse models.,2020/10/18,34,Rapid lipid deposition in endo,Common carotid arteries of apoE-/-, LPL+/- (ELK)mice (A) and apoE-/-, LPL+/+ (EK)mice (B) 8 weeks after ferric chloride injury,2020/10/18,35,Common carotid arteries of apo,neointima formation after carotid artery injury by FeCl,3,for,8 weeks,ELK,carotid artery, H,&E staining,EK,noninjured,injured,2020/10/18,36,neointima formation after caro,Mean Area of Intimal and Medial Cross-sections of EK and ELK Mice 8 Weeks after Injury,EK,ELK,*,*,media,intimal,0,2,4,6,8,10,Mean Area (um,2,X10,4,),2020/10/18,37,Mean Area of Intimal and Media,lipid deposit after carotid artery injury by FeCl,3,for,8,weeks,ELK,EK,carotid artery counterstained with ORO and haematoxylin,injured,noninjured,2020/10/18,38,lipid deposit after carotid ar,lipid deposit after carotid artery injury by FeCl,3,for,4,weeks,ELK,EK,carotid artery counterstained with ORO and haematoxylin,noninjured,injured,2020/10/18,39,lipid deposit after carotid ar,Mac3 staining （8 weeks sample）,ELK,EK,V W Factor Staining,2020/10/18,40,Mac3 staining （8 weeks sample,*,*,NS,Plasma TG of ELK and EK Mice Fed HFD,0,100,200,300,ELK,EK,TG (mg/dl),0,Week 4,Week 8,2020/10/18,41,*NSPlasma TG of ELK and EK,Plasma TC levels of ELK and EK Mice Fed HFD,0,250,500,750,1000,ELK,EK,TC mg/dl,0,Week 4,Week 8,2020/10/18,42,Plasma TC levels of ELK and EK,Accelerated atherogenesis in LPL deficient,mice as assessed by FeCl3 arterial injury,in ApoE knockout background,2020/10/18,43,Accelerated atherogenesis in,Pancreatitis in minks with LPL deficiency,A.,HE stain of pancreas of normal (top left) and affect area;,B.,HE stain of section full with macrophages;,C.,Sudan IV stain indicating lipid accumulation. (Mag.X425),Christophersen et al, JLR. 38:837, 1997,2020/10/18,44,Pancreatitis in minks with LPL,normal,infiltration,hemorrhage,necrosis,Spontaneous pancreatitis in LPL-/- mice,（HE X200）,2020/10/18,45,normalinfiltrationhemorrhagene,WT,4 month,LK,4 month,（Sirus Red X200）,Spontaneous pancreatitis in LPL-/- mice,2020/10/18,46,WT LK （Sirus Red X200）Sp,Ctl Mouse, C57B6,L-arginine (ip at 2mg/g BW), 72h,L-arginine (ip at 4mg/g BW), 24h,L-arginine (ip at 3mg/g BW), 72h,Pathology in L-Arg induced Acute Pancreatitis,2020/10/18,47,Ctl Mouse, C57B6L-arginine (i,Changes of serum amylase,n=4,*,*,2020/10/18,48,Changes of serum amylasen=4 *,Increased susceptibility to pancreatitis,LPL genotype,+ - + -,L-Arg,Induction,- - + +,* *,2020/10/18,49,Increased susceptibility to pa,Neurological defects in LPL deficient mice?,Day1 Day2 Day3 Day4 Day5,Seconds,spent to find under water platform,wt,L0,*,100,75,50,25,0,Water Maze performance,*,2020/10/18,50,Neurological defects in LPL,Hippocampus Neuron Stained with MAP-2,WT,LPL-/-,2020/10/18,51,Hippocampus Neuron Stained wit,Hippocampus Neuron Stained with Tau-2,WT,LPL-/-,2020/10/18,52,Hippocampus Neuron Stained wit,Acknowledgement,北京大学心血管研究所,黄薇,赵铁强,高松,朱露,王景瑜,2020/10/18,53,Acknowledgement北京大学心血管研究所2020/,2020/10/18,54,2020/10/1854,谢谢您的聆听与观看,THANK YOU FOR YOUR GUIDANCE.,感谢阅读！为了方便学习和使用，本文档的内容可以在下载后随意修改，调整和打印。欢迎下载！,汇报人：,XXX,日期：,20XX,年,XX,月,XX,日,谢谢您的聆听与观看THANK YOU FOR YOUR GU,
展开阅读全文