miR-10a regulation of regional arterial endothelial phenotypes in atherosclerosis

miR-10a对动脉粥样硬化区域动脉内皮表型的调节

基本信息

批准号：
8111489
负责人：
Yun Fang
金额：
$ 8.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111489
关键词：
Adult Advisory Committees Affect American Heart Association Animal Model Arterial Fatty Streak Arteries Atherosclerosis Biochemical Biogenesis Biological Markers Biology Biomedical Engineering Biomedical Research Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular system Cell Line Cells Chronic Complex Development Development Plans Diabetes Mellitus Disease Doctor of Philosophy Endoplasmic Reticulum Endothelial Cells Endothelium Environment Etiology Exhibits Family suidae Functional disorder Genes Genomics Goals Heterogeneity Hypertension In Vitro Inflammation Inflammatory Kidney Knowledge Laboratories Lesion Link MAP3K7 gene MAP3K7IP1 gene Mediating Mediation Mentors MicroRNAs Molecular Analysis Molecular Biology Molecular Profiling Muscle Myocardial Infarction Natural History Nuclear Translocation Nucleic Acids Nucleotides Pathology Pathway interactions Pennsylvania Phase Phenotype Positioning Attribute Post-Transcriptional Regulation Predisposition Proteins Regulation Regulator Genes Research Research Proposals Reticulum Role Science Site Small RNA Stimulus Stream Stroke System Systems Biology Testing Therapeutic Intervention Training Transgenic Mice Universities Up-Regulation Work aortic arch athero susceptible atherogenesis career development cell growth regulation cohort design endoplasmic reticulum stress experience functional genomics hemodynamics hypercholesterolemia in vivo lipoprotein disorder mouse model p65 post-doctoral training programs research and development response skills transcription factor

Adult Advisory Committees Affect American Heart Association Animal Model Arterial Fatty Streak Arteries Atherosclerosis Biochemical Biogenesis Biological Markers Biology Biomedical Engineering Biomedical Research Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular system Cell Line Cells Chronic Complex Development Development Plans Diabetes Mellitus Disease Doctor of Philosophy Endoplasmic Reticulum Endothelial Cells Endothelium Environment Etiology Exhibits Family suidae Functional disorder Genes Genomics Goals Heterogeneity Hypertension In Vitro Inflammation Inflammatory Kidney Knowledge Laboratories Lesion Link MAP3K7 gene MAP3K7IP1 gene Mediating Mediation Mentors MicroRNAs Molecular Analysis Molecular Biology Molecular Profiling Muscle Myocardial Infarction Natural History Nuclear Translocation Nucleic Acids Nucleotides Pathology Pathway interactions Pennsylvania Phase Phenotype Positioning Attribute Post-Transcriptional Regulation Predisposition Proteins Regulation Regulator Genes Research Research Proposals Reticulum Role Science Site Small RNA Stimulus Stream Stroke System Systems Biology Testing Therapeutic Intervention Training Transgenic Mice Universities Up-Regulation Work aortic arch athero susceptible atherogenesis career development cell growth regulation cohort design endoplasmic reticulum stress experience functional genomics hemodynamics hypercholesterolemia in vivo lipoprotein disorder mouse model p65 post-doctoral training programs research and development response skills transcription factor

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项目摘要

DESCRIPTION (provided by applicant): The proposal outlines an integrated research and career development plan for Yun Fang, Ph.D to complete postdoctoral training in the laboratory of Dr. Peter Davies and transition to an independent academic position by establishing a multi-disciplinary research program in cardiovascular pathophysiology. The PI is currently an American Heart Association Fellow who is trained in the fields of molecular biology, bioengineering, and vascular biology. During the 2 year mentored period, the PI will receive additional academic guidance from the mentor and the advisory committee at the University of Pennsylvania. The career development plan is designed to equip the PI with necessary knowledge and skills in biomedical research for a successful transition as an independent academician, leading to a RO1 as the R00 phase of the work progresses. The overall research goal is to determine the role of microRNA-10a (miR-10a) in mediating endothelial phenotypes in relation to the initiation and development of atherosclerosis. MicroRNA-mediated post-transcriptional regulation is poorly understood in arterial biology and pathology. Preliminary studies conducted by the K99 PI demonstrate that differential topographic expression of miR-10a in distinct arterial sites significantly contributes to the endothelial heterogeneity associated with susceptibility to atherosclerosis. Notably, endothelial miR-10a is significantly suppressed in vivo in athero-susceptible regions exposed to disturbed blood flow in a large animal model. Further functional genomics and biochemical analyses demonstrated that miR-10a promotes the athero-protective phenotype in endothelial cells by suppressing NF-B-mediated inflammation (PNAS in press). The research proposal tests the overall hypothesis that flow and/or hypercholesterolemia-sensitive miR-10a dynamically modulates endothelial phenotypes in the initiation and progression of atherosclerosis. Aim 1 will test the hypothesis that athero-protective miR-10a suppresses endothelial inflammation and Endoplasmic Reticulum stress (ER stress) by direct inhibition of a cohort of positive NF-B and Unfolded Protein Response (UPR) responsive molecules. Aim 2 will test the hypothesis that athero- relevant hemodynamic force regulates mechano-sensitive transcription factors, leading to differential control of endothelial miR-10a biogenesis at athero-susceptible and athero-protected regions in vivo. And Aim 3 will develop a transgenic mouse model that exhibits inducible expression of endothelial miR-10a to demonstrate the causality of endothelial miR-10a expression and atherosclerosis, thereby testing in vivo the hypothesis that athero-protective miR-10a inhibits endothelial inflammation and ER stress, alleviating atherosclerotic burden. The goal will be achieved by integrating system biology and molecular analysis in both in vitro and in vivo systems, leading to mechanistic understandings of the down-stream gene networks and up-stream regulators of endothelial miR-10a with respect to atherosclerosis. PUBLIC HEALTH RELEVANCE: Atherosclerosis causes most cardiovascular diseases such as heart attack and stroke. The plaques develop in predictable sites of arteries which are susceptible to disease. The sites have unusual blood flow which affects the endothelial cells lining the artery and predisposes them to lesions. My studies analyze the regulatory role of small nucleic acids called microRNAs in cells in relation to atherosusceptibility and blood flow. We hope to define microRNA-related targets for therapeutic intervention in cardiovascular disease.

描述（由申请人提供）：该提案概述了Yun Fang博士的一项综合研究和职业发展计划，以通过彼得·戴维斯博士的实验室完成博士后培训，并通过在心血管病理生理学中建立多学科研究计划，通过建立多学科研究计划。 PI目前是美国心脏协会研究员，在分子生物学，生物工程和血管生物学领域接受培训。在两年的指导期间，PI将获得宾夕法尼亚大学导师和咨询委员会的额外学术指导。职业发展计划旨在为PI提供生物医学研究中必要的知识和技能，以成功地作为独立院士过渡，从而导致RO1随着R00阶段的发展。总体研究目标是确定microRNA-10A（miR-10a）在介导内皮表型中与动脉粥样硬化的起始和发育有关的作用。在动脉生物学和病理学中，microRNA介导的转录后调节尚不清楚。 K99 PI进行的初步研究表明，不同动脉部位中miR-10a的差异地形表达显着促进了与动脉粥样硬化易感性相关的内皮异质性。值得注意的是，在大型动物模型中暴露于血液流动受到干扰的动脉敏感区域中，内皮miR-10a在体内被显着抑制。进一步的功能基因组学和生化分析表明，miR-10a通过抑制NF-B介导的炎症（PRESS中的PNA）来促进内皮细胞中的动脉保护表型。研究提案检验了流动和/或高胆固醇敏感的miR-10a在动脉粥样硬化的启动和进展中动态调节内皮表型的总体假设。 AIM 1将通过直接抑制阳性NF-B和展开的蛋白质反应（UPR）响应性分子来抑制内皮炎症和内质网应激（ER应激）的假设。 AIM 2将检验以下假设：动脉粥样硬化相关的血液动力学调节机械敏感的转录因子，从而导致对动脉粥样敏感和受动脉粥样硬化的区域的内皮miR-10a生物发生的差异控制。 AIM 3将开发一个转基因小鼠模型，该模型表现出可诱导的内皮miR-10a表达，以证明内皮miR-10a表达和动脉粥样硬化的因果关系，从而在体内测试了动脉粥样硬化的miR-10a抑制内皮炎症和抗压力，毒死的假设。该目标将通过在体外和体内系统中整合系统生物学和分子分析来实现，从而导致对下游基因网络和内皮miR-10A的上流调节剂的机械理解，相对于动脉粥样硬化。公共卫生相关性：动脉粥样硬化会导致大多数心血管疾病，例如心脏病发作和中风。这些斑块在容易受到疾病的动脉的可预测部位发展。这些部位具有异常的血流，会影响动脉内衬的内皮细胞，使它们易于病变。我的研究分析了称为microRNA的小核酸在细胞中与动脉粥样硬化性和血流有关的调节作用。我们希望定义与MicroRNA相关的靶标，以用于心血管疾病的治疗干预。