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: 8653985
• 负责人: Yun Fang
• 金额: $ 24.37万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-18 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653985
• 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; abstracting; aortic arch; athero susceptible; atherogenesis; career development; cell growth regulation; cohort; design; endoplasmic reticulum stress; endothelial dysfunction; experience; functional genomics; hemodynamics; hypercholesterolemia; in vivo; lipoprotein disorder; mouse model; p65; post-doctoral training; programs; research and development; response; skills; transcription factor

Abstract 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.

摘要 该提案概述了一个综合的研究和职业发展计划，为云芳博士完成 在彼得·戴维斯博士的实验室进行博士后培训，并过渡到独立的学术职位 通过建立心血管病理生理学的多学科研究计划。目前，PI是 美国心脏协会研究员，在分子生物学、生物工程和 血管生物学在2年的指导期内，PI将获得来自 导师和顾问委员会在宾夕法尼亚大学。职业发展计划是 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 作为一个独立的院士，导致一个RO 1作为R 00阶段的工作进展。整体 研究目的是确定microRNA-10a（miR-10a）在介导内皮细胞表型中的作用， 与动脉粥样硬化的发生和发展有关。MicroRNA介导的转录后调控 在动脉生物学和病理学中知之甚少。K99 PI进行的初步研究 证明miR-10a在不同动脉部位的差异地形表达显著有助于 与动脉粥样硬化易感性相关的内皮异质性。值得注意的是，内皮miR-10a 在体内暴露于受干扰血流的动脉粥样硬化易感区域中， 动物模型进一步的功能基因组学和生物化学分析表明，miR-10a促进 通过抑制NF-B介导的炎症在内皮细胞中的动脉粥样硬化保护表型（PNAS in Press）。该研究计划测试了流动和/或高胆固醇血症敏感的总体假设， miR-10a在血管内皮细胞凋亡的发生和发展中动态调节内皮细胞表型 动脉粥样硬化目的1将检验动脉粥样硬化保护性miR-10a抑制内皮细胞增殖的假设。 炎症和内质网应激（ER应激）通过直接抑制一组阳性NF-B 和未折叠蛋白质应答（UPR）应答分子。目标2将检验动脉粥样硬化的假设， 相关的血流动力学力调节机械敏感的转录因子，导致差异控制， 在体内动脉粥样硬化易感区域和动脉粥样硬化保护区域的内皮miR-10a生物合成。Aim 3将 开发一种显示内皮miR-10a可诱导表达的转基因小鼠模型，以证明 内皮细胞miR-10a表达与动脉粥样硬化的因果关系，从而在体内验证以下假设： 动脉粥样硬化保护性miR-10a抑制内皮炎症和ER应激，减轻动脉粥样硬化负担。 这一目标将通过在体外和体内整合系统生物学和分子分析来实现 系统，导致下游基因网络和上游调节器的机械理解 与动脉粥样硬化的关系。