小分子RNA与心血管疾病.ppt
《小分子RNA与心血管疾病.ppt》由会员分享,可在线阅读,更多相关《小分子RNA与心血管疾病.ppt(41页珍藏版)》请在三一文库上搜索。
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,MiroRNAs,MicroRNAs (miRNAs) are a novel class of endogenous, small, noncoding RNAs that regulate gene expression. Mature miRNAs are 18- to 24-nucleotide(nt)-long.
2、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.,Pathway of Genetic Information Flow and RNA “revolution”,1.The standard pathway of information flow in a ce
3、ll. 2. DNA Transcription and RNA products 3. The first RNA revolution.,Discovery of miRNA - The second RNA “revolution”,Discovery 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 mi
4、RNA represent the second RNA revolution (Kong et al. Genomics Proteomics Bioinformatics. 2005;3: 62-72).,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 prod
5、uced from long double-stranded (bimolecular) RNAs or long hairpins, often 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
6、 expression.,Biogenesis of miRNAs and their molecular mechanism for gene regulation,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 miRNAs are important regulators for cell growt
7、h, differentiation, and apoptosis. Therefore, miRNAs could be the important endogenous regulators in normal development, physiology, as well as in disease.,miRNAs in diseases,Consequently, dysregulation of miRNA function may lead to human diseases. In this respect, the most exciting research area is
8、 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 demonstrated that miRNAs are aberrantly expressed in diverse cancers. The recent advances in the research of m
9、iRNAs 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 profiles. Second, multiple miRNAs are dysregulated in cancers. Third,miRNAs are thought to function a
10、s 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 critical for cancer research,MiRNAs in cardiovascular disease,Proliferative vascular disease has long been
11、 the leading cause of death in developed countries. Although miRNAs are highly expressed in the vascular system, the roles of these miRNAs in vascular disease are unknown. As vascular disease share some similar cellular events and molecular mechanisms with cancer, we hypothesize that miRNAs may play
12、 important roles in vascular disease.,Animal Model Selection,Vascular neointimal lesion formation. Neointimal formation is the common pathological lesion in atherosclerosis, restenosis, diabetic vascular complication and transplant vascular disease.,Hypothesis,Cell growth (proliferation) and apoptos
13、is are key cellular events in 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 muscl
14、e cell growth and/or apoptosis.,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 with neointimal lesion formati
15、on? 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 the molecular mechanisms resp
16、onsible for miRNA-mediated effect on neoinimal formatiom?,Rat carotid artery balloon injury,To determine the expression changes of miRNAs in the vascular wall with neointimal formation, we applied the well-established rat carotid artery balloon injury model in my laboratory. In which, rat (Sprague-D
17、awley, 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.,MiRNA expression signature in normal rat carotid artery,MiRNAs are aberrantly expressed in rat carotid arteries
18、 after angioplasty,Compared with normal uninjured arteries, microarray analysis demonstrated that aberrant 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.
19、01; 60 miRNAs were upregulated, and 53 miRNAs were downregulated. At 14 days after injury, 110 of the 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.,The time cours
- 配套讲稿:
如PPT文件的首页显示word图标,表示该PPT已包含配套word讲稿。双击word图标可打开word文档。
- 特殊限制:
部分文档作品中含有的国旗、国徽等图片,仅作为作品整体效果示例展示,禁止商用。设计者仅对作品中独创性部分享有著作权。
- 关 键 词:
- 分子 RNA 心血管疾病
链接地址:https://www.31doc.com/p-2792342.html