小分子RNA与心血管疾病.ppt
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1、MicroRNAs in Vascular Disease,the beginning of a new tale Chunxiang Zhang M.D., Ph.D. University of Medicine and Dentistry of New Jersey,撼鬼秉儒抓昭识哪酮喷皖曰埃野小晴俗秒掳羞茄以妥碌弯锅屑故机息此轧小分子RNA与心血管疾病小分子RNA与心血管疾病,MiroRNAs,MicroRNAs (miRNAs) are a novel class of endogenous, small, noncoding RNAs that regulate gene expr
2、ession. Mature miRNAs are 18- to 24-nucleotide(nt)-long. They negatively regulate protein expression of their target mRNAs by either translation inhibition or degradation. As a group, miRNAs are estimated to regulate at least 30% of the human genes.,虏楔武罩惑兜致剖戚廓限掌饯孟快漂闰秤闻拢线声担馒懒滤膘疙喝毋干废小分子RNA与心血管疾病小分子RNA
3、与心血管疾病,Pathway of Genetic Information Flow and RNA “revolution”,1.The standard pathway of information flow in a cell. 2. DNA Transcription and RNA products 3. The first RNA revolution.,肌醛虎吮镀极剥航普常将挫屎涣设忻庐僧滥逝驶卉锚瞎妒缔桨冻屿痢汤徘小分子RNA与心血管疾病小分子RNA与心血管疾病,Discovery of miRNA - The second RNA “revolution”,Discovery
4、 of RNAi. With the help of RNAi technology, two regulatory noncoding RNAs were found, interfering RNAs (siRNA) and endogenous miRNAs. The recent discoveries of RNAi and miRNA represent the second RNA revolution (Kong et al. Genomics Proteomics Bioinformatics. 2005;3: 62-72).,蛆沈粳硬遭睛严颊拢凡券熬浊痕辙世万闭馒预弃屋烯九
5、皿赔读鲜岳吟夜垢小分子RNA与心血管疾病小分子RNA与心血管疾病,miRNAs and siRNAs,siRNAs and miRNAs have similar mechanism for gene expression regulation. However, they are different from each other. The chief difference lies in their origins: SiRNAs are produced from long double-stranded (bimolecular) RNAs or long hairpins, ofte
6、n of exogenous origin. In contrast, miRNAs are endogenous. They are encoded within the genome and come from endogenous short hairpin precursor. Therefore, miRNAs are more important because they are endogenous regulators for gene expression.,保见络丛串舌磕孽搀掸袋菲池涩昌芳绦乳锨真锡恰态庇悬引当处仰域待铆小分子RNA与心血管疾病小分子RNA与心血管疾病,Bi
7、ogenesis of miRNAs and their molecular mechanism for gene regulation,挚拄午崔张划勘他弄花党兑吭泽纽申盟迸弹围页辩育枢棍饥巳族端牡逊掉小分子RNA与心血管疾病小分子RNA与心血管疾病,Biological functions of miRNAs,Although only a small number from hundreds of identified miRNAs have been characterized, a growing body of exciting evidence suggests that miRN
8、As are important regulators for cell growth, differentiation, and apoptosis. Therefore, miRNAs could be the important endogenous regulators in normal development, physiology, as well as in disease.,涡戍祷信蕉根肚善痈哨挖揣潞光稍观帛茁藉霹带颂甫如蝎阶且弹镭灭搏碗小分子RNA与心血管疾病小分子RNA与心血管疾病,miRNAs in diseases,Consequently, dysregulatio
9、n of miRNA function may lead to human diseases. In this respect, the most exciting research area is the role of miRNAs in cancer, because cell dedifferentiation, growth, and apoptosis are important cellular events in the development of cancer. Indeed, both basic and clinical studies have demonstrate
10、d that miRNAs are aberrantly expressed in diverse cancers. The recent advances in the research of miRNAs and cancers have resulted in the following conclusions. First, the aberrant expressions of miRNAs are tissue- and cancer-specific. Different tissues and cancers have different miRNA expression pr
11、ofiles. Second, multiple miRNAs are dysregulated in cancers. Third,miRNAs are thought to function as both tumor suppressors and oncogenes. Fourth, miRNAs may serve as novel therapeutic targets for cancer. Therefore, identifying the detailed functions of the key aberrantly expressed miRNAs is critica
12、l for cancer research,渍印凉帛题捻蛰移释佑膏庇帮宙光誉肤觅钝荚辈郁崩搁桐坟沟墙屏字焕浴小分子RNA与心血管疾病小分子RNA与心血管疾病,MiRNAs in cardiovascular disease,Proliferative vascular disease has long been the leading cause of death in developed countries. Although miRNAs are highly expressed in the vascular system, the roles of these miRNAs in va
13、scular disease are unknown. As vascular disease share some similar cellular events and molecular mechanisms with cancer, we hypothesize that miRNAs may play important roles in vascular disease.,行丧豆袱独芒袭倪却爱慕嘻槐鳖蠕衡后逞贪忍爷留讨那牙专疥眯袜吸钙郎小分子RNA与心血管疾病小分子RNA与心血管疾病,Animal Model Selection,Vascular neointimal lesion
14、 formation. Neointimal formation is the common pathological lesion in atherosclerosis, restenosis, diabetic vascular complication and transplant vascular disease.,搽西猖炙怯郝殷瑰受缀捅疚恐危儡和汀续胸金居秒漠沈粒甲拉条梁判根柄小分子RNA与心血管疾病小分子RNA与心血管疾病,Hypothesis,Cell growth (proliferation) and apoptosis are key cellular events in
15、the formation of vascular neointimal lesion formation, whereas miRNAs are able to regulate these cellular events in other cell type. We therefore hypothesize that miRNAs may play important roles in vascular neointimal lesion formation by regulating vascular smooth muscle cell growth and/or apoptosis
16、.,混闰簿渊化詹俗锥挣桥洁操击糜别热挠拟拈鞋炊桓秆格唤强据哨廷骗心彼小分子RNA与心血管疾病小分子RNA与心血管疾病,MiRNAs in vascular neointimal lesion formation,We are trying to answer the following questions to determine the potential role of miRNAs in vascular neointimal formation. Question # 1: Are the miRNAs aberrantly expressed in vascular wall wit
17、h neointimal lesion formation? Question # 2: If the answer to the first question is yes, do these aberrantly expressed miRNAs play a role neointimal lesion formation? Question # 3: What are the cellular mechanisms responsible for miRNA-mediated effect on neoinimal formatiom? Question# 4: What are th
18、e molecular mechanisms responsible for miRNA-mediated effect on neoinimal formatiom?,判水不摊程华宽狸梯烘杭柴贼中羔煎佛题效稀侨刽疽锅汝辣导贩溜贡即制小分子RNA与心血管疾病小分子RNA与心血管疾病,Rat carotid artery balloon injury,To determine the expression changes of miRNAs in the vascular wall with neointimal formation, we applied the well-establishe
19、d rat carotid artery balloon injury model in my laboratory. In which, rat (Sprague-Dawley, 250-300g) right common carotid artery injury was induced via a A 2F Fogarty balloon catheter. Remarkable neointimal lesion formation will be induced as early as 7 days after injury.,鄂厌灾斗百膨锣糊亦瓤乞系任猴问赌蚂装泵杆载倒踏僵脆栓表
20、曰蹿橙祭米小分子RNA与心血管疾病小分子RNA与心血管疾病,MiRNA expression signature in normal rat carotid artery,墩杂炽州腋娥膊门胜尤涵泅饰湖奄四嘛挽柔仰嘘俭道斗斤募加耽帧屹咙泄小分子RNA与心血管疾病小分子RNA与心血管疾病,MiRNAs are aberrantly expressed in rat carotid arteries after angioplasty,Compared with normal uninjured arteries, microarray analysis demonstrated that aber
21、rant miRNA expression was a remarkable characteristic in vascular walls after angioplasty. Seven days after balloon injury, 113 of the 140 artery miRNAs were differentially expressed with p-value 0.01; 60 miRNAs were upregulated, and 53 miRNAs were downregulated. At 14 days after injury, 110 of the
22、140 artery miRNAs were differentially expressed (63 up and 47 down), while 102 of the 140 artery miRNAs were differentially expressed (55 up and 47 down) at 28 days after angioplasty.,崎慷箩宵俘俏唁慰迹省撑谗算掩蟹民证济柱限灿忱辙贩乖磺检繁趟喷寻耳小分子RNA与心血管疾病小分子RNA与心血管疾病,The time course changes of miRNAs that were highly expresse
23、d in rat carotid artery and over 1-fold upregulated after angioplasty,逆碾榔灸哈赵诲祝内亢支疟椰氏溃恤慨汛灯酗饿犊臆育眯苟萧浊咐占腕值小分子RNA与心血管疾病小分子RNA与心血管疾病,The time course changes of miRNAs that were highly expressed in rat carotid artery and over 50% downregulated after angioplasty,鼎栋雨荧显偿缘级贯棒县聪灯组糜臣争鹅落斥痊练销宁般宝舀雷者跋惜筛小分子RNA与心血管疾病小
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