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

• 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
• 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

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)：该提案概述了方运博士的综合研究和职业发展计划，以在Peter Davies博士的实验室完成博士后培训，并通过建立心血管病理生理学的多学科研究计划过渡到独立的学术职位。PI目前是美国心脏协会的会员，在分子生物学、生物工程和血管生物学领域接受过培训。在两年的辅导期内，PI将从导师和宾夕法尼亚大学的咨询委员会那里获得额外的学术指导。职业发展计划旨在使PI具备生物医学研究方面的必要知识和技能，以便成功过渡为独立院士，随着工作的R00阶段的进展而产生RO1。总的研究目标是确定microRNA-10a(miR-10a)在介导内皮细胞表型与动脉粥样硬化的发生和发展中的作用。在动脉生物学和病理学中，对microRNA介导的转录后调控知之甚少。K99PI进行的初步研究表明，miR-10a在不同动脉部位的不同地形表达显著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，暴露于血流紊乱的动脉粥样硬化敏感区域的内皮miR-10a在体内显著受到抑制。进一步的功能基因组学和生化分析表明，miR-10a通过抑制核因子-B介导的炎症(PNAS)促进内皮细胞的动脉粥样硬化保护表型。这项研究提案测试了总体假设，即流动和/或高胆固醇血症敏感的miR-10a在动脉粥样硬化的发生和发展中动态调节内皮表型。目的1验证动脉粥样硬化保护性miR-10a通过直接抑制一组阳性的核因子-B和未折叠蛋白反应(UPR)反应分子而抑制内皮细胞炎症和内质网应激(ER应激)的假设。目的2验证动脉粥样硬化相关血流动力调节机械敏感转录因子的假说，从而导致体内动脉粥样硬化易感区域和动脉粥样硬化保护区域内皮细胞miR-10a生物发生的差异控制。Aim 3将建立可诱导表达内皮miR-10a的转基因小鼠模型，以证明内皮miR-10a表达与动脉粥样硬化的因果关系，从而在体内验证动脉粥样硬化保护性miR-10a抑制内皮炎症和内质网应激，减轻动脉粥样硬化负担的假说。这一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，从而从机制上理解内皮细胞miR-10a的下游基因网络和上游调控因子与动脉粥样硬化的关系。 公共卫生相关性：动脉粥样硬化导致大多数心血管疾病，如心脏病发作和中风。这些斑块在易受疾病影响的动脉的可预测位置发展。这些部位有异常的血流，影响到动脉内的内皮细胞，使它们容易受到损害。我的研究分析了细胞中被称为microRNAs的小核酸在与动脉粥样硬化易感性和血流相关的调节作用。我们希望为心血管疾病的治疗干预定义与microRNA相关的靶点。