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.

抽象的 该提案概述了Yun Fang博士的综合研究和职业发展计划 彼得·戴维斯（Peter Davies）博士实验室的博士后培训，并过渡到独立的学术职位 通过建立心血管病理生理学中的多学科研究计划。 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。在两年的指导期内，PI将获得 宾夕法尼亚大学的导师和咨询委员会。职业发展计划是 旨在为PI配备生物医学研究的必要知识和技能，以成功过渡 作为一名独立的院士，随着R00阶段的发展，导致RO1。总体 研究目标是确定microRNA-10A（miR-10a）在介导内皮表型中的作用 与动脉粥样硬化的启动和发展有关。 microRNA介导的转录后调节 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在不同动脉部位中miR-10a的差分表达显着贡献 对于与动脉粥样硬化的易感性相关的内皮异质性。值得注意的是，内皮miR-10a 在暴露于大型血液流动的动脉敏感区域中，体内受到显着抑制 动物模型。进一步的功能基因组学和生化分析表明，miR-10a促进 通过抑制NF-B介导的炎症（PNAS中的PNAS），内皮细胞中的动脉保护表型 按）。研究建议检验了流动和/或高胆固醇敏感的总体假设 miR-10a在开始和进展中动态调节内皮表型 动脉粥样硬化。 AIM 1将检验以下假设，即动脉保护miR-10a抑制内皮 通过直接抑制阳性NF-B的炎症和内质网应激（ER应激） 和展开的蛋白质反应（UPR）反应性分子。 AIM 2将检验以下假设 相关的血液动力力调节机械敏感的转录因子，导致对 在体内触及和动脉粥样硬化的区域处的内皮miR-10a生物发生。 AIM 3将 开发一种转基因小鼠模型，该模型表现出内皮miR-10a的诱导表达以证明 内皮miR-10a表达和动脉粥样硬化的因果关系，从而在体内检验以下假设： 动脉保护miR-10a抑制内皮炎症和ER压力，减轻动脉粥样硬化负担。 该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，导致对下游基因网络和上流调节器的机械理解 关于动脉粥样硬化的内皮miR-10a。