Systems Biology Analyses for Hemodynamic Regulation of Vascular Homeostasis

血管稳态血流动力学调节的系统生物学分析

基本信息

批准号：
8332732
负责人：
SHU CHIEN
金额：
$ 109.07万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-24 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8332732
关键词：
Animals Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Apoptosis Area Arterial Fatty Streak Atherosclerosis Bioinformatics Biological Assay Blood Vessels Cardiovascular Diseases Cardiovascular system Cell physiology Cells Chromosome Mapping Cues Data Disease Endothelial Cells Event Figs - dietary Gene Expression Gene Expression Regulation Genes Health Homeostasis In Vitro Inflammation Inflammatory Knock-out Knowledge Lead Leukocytes Maintenance Maps Measurement Mechanics Messenger RNA Modeling Molecular Molecular Profiling Mus Nature Output Oxidation-Reduction Pathway interactions Pattern Phenotype Physiological Play Prevention Procedures Process Proteins Proteomics Regulation Resistance Resolution Role Signal Pathway Signal Transduction Signaling Molecule Signaling Pathway Gene Simulate Small Interfering RNA Staging Stress System Systems Biology Thoracic aorta Time Tissues Transcriptional Regulation Translational Regulation Trees Vascular Diseases Vascular Endothelial Cell Wound Healing aortic arch base disorder prevention hemodynamics in vivo inhibitor/antagonist insight loss of function monocyte network models novel oxidation protective effect reconstruction research study response shear stress

项目摘要

DESCRIPTION (provided by applicant): The focal nature of the atherosclerotic lesions indicates that hemodynamic forces are critical for the regulation of vascular homeostasis in health and disease. Responses of vascular endothelial cells (ECs) to hemodynamic forces play significant roles in such regulations. In vivo studies implicate that the ECs in branch points express pro-atherogenic phenotypes. In contrast, ECs in the straight parts of the arterial tree are exposed to high shear flow with a large net forward direction, and these regions are generally spared from atherosclerosis. The in vitro studies by others and us suggest that steady and pulsatile shear stresses (PS) with a net forward direction, which simulates the flow condition at the straight part of the arterial tree, induce genes involved in anti-proliferation, anti-oxidation anti-inflammation, and maintenance of vascular tone, with athero-protective effects such as reduction of cell turnover, prevention of white cell recruitment, promotion of wound healing, and adaptive remodeling. In contrast, oscillatory shear stress (OS) without a significant forward direction is atherogenic by activating pro-proliferative, pro-oxidative, and pro-inflammatory genes. We hypothesize that, while PS and OS may activate similar signaling events at the initial stage, the results will diverge with time. Time-dependent mapping of the signal networks will lead to temporal resolution of the gene expression profiles, hence the differential functional consequences of PS vs. OS. In this proposed project, we will examine the signaling, transcriptional regulations, and functional phenotypes of ECs under PS and OS over time. Mapping the differential pathways under these flow conditions requires the use of systems biology approaches that provides a comprehensive mechanistic and network perspective on the diferential responses to stresses. In order to systematically map the flow-regulation of EC functions, we propose the following specific aims: (1) To establish the temporal map of EC signaling events under PS vs, OS. (2) To investigate the transcriptional regulations of EC gene expression under PS vs, OS. (3) To examine the temporal resolution of phenotypic responses of ECs under PS vs, OS. (4) To integrate molecular events and EC functions by reconstruction of signaling models. (5) To validate the defined EC signaling events and gene expressions in mouse arterial tree. Under these Specific Aims, we will conduct experiments systematically to obtain the data necessary for the systems biology analyses to construct the molecular and pathway models for the physiological and pathological regulations of EC molecular events and functional consequences. This integrative and collaborative systems biology approach will generate new insights into the intricate process of mechanotransduction by which different flow patterns modulate homeostasis in the arterial wall. These findings will greatly enhance our understanding of the molecular and mechanical bases of atherosclerosis, a major pathophysiological event in cardiovascular diseases. PUBLIC HEALTH RELEVANCE: We propose to use the systems biology approach combining the experimental procedures and bioinformatics analyses to understand the hemodynamic regulation of vascular functions. The resultant mechanistic and pathway models will provide critical information on the mechanisms of atherosclerosis, a major vascular disease impairing cardiovascular health. The study will also provide novel knowledge for disease prevention, treatments, and management.

描述（由申请人提供）：动脉粥样硬化病变的局灶性表明血流动力学对于健康和疾病中血管稳态的调节至关重要。血管内皮细胞（EC）对血流动力学的反应在此类调节中发挥着重要作用。体内研究表明分支点的 EC 表达促动脉粥样硬化表型。相比之下，动脉树笔直部分的 EC 是暴露于具有大净前向的高剪切流下，这些区域通常不会发生动脉粥样硬化。我们和其他人的体外研究表明，具有净前向的稳态和脉动剪切应力（PS）模拟动脉树直线部分的流动条件，诱导参与抗增殖、抗氧化和抗氧化的基因。 -炎症和维持血管张力，具有动脉粥样硬化保护作用，例如减少细胞更新、防止白细胞募集、促进伤口愈合和适应性重塑。相反，没有明显前进方向的振荡剪切应力（OS）会通过激活促增殖、促氧化和促炎症基因而导致动脉粥样硬化。我们假设，虽然 PS 和 OS 在初始阶段可能会激活类似的信号事件，但结果会随着时间的推移而出现差异。信号网络的时间依赖性映射将导致基因表达谱的时间分辨率，因此 PS 与 OS 的功能结果不同。在这个拟议的项目中，我们将随着时间的推移检查 PS 和 OS 下 EC 的信号传导、转录调控和功能表型。绘制这些流动条件下的差异路径需要使用系统生物学方法，该方法为对压力的差异响应提供全面的机制和网络视角。为了系统地绘制 EC 功能的流量调节图，我们提出以下具体目标：（1）建立 PS 与 OS 下 EC 信号事件的时间图。 (2)探讨PS与OS下EC基因表达的转录调控。 (3) 检查 PS 与 OS 下 EC 表型反应的时间分辨率。 (4)通过重建信号模型来整合分子事件和EC功能。 (5) 验证小鼠动脉树中定义的 EC 信号事件和基因表达。在这些具体目标下，我们将系统地进行实验，以获得系统生物学分析所需的数据，以构建EC分子事件和功能后果的生理和病理调控的分子和途径模型。这种综合协作的系统生物学方法将为复杂的力转导过程产生新的见解，不同的流动模式通过该过程调节动脉壁的稳态。这些发现将极大地增强我们对动脉粥样硬化（心血管疾病的主要病理生理学事件）的分子和机械基础的理解。公共健康相关性：我们建议使用系统生物学方法结合实验程序和生物信息学分析来了解血管功能的血流动力学调节。由此产生的机制和途径模型将提供有关动脉粥样硬化机制的关键信息，动脉粥样硬化是一种损害心血管健康的主要血管疾病。该研究还将为疾病预防、治疗和管理提供新知识。