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

• 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
• 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

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焦点表明，血液动力学对于调节健康和疾病中血管稳态至关重要。血管内皮细胞（EC）对血液动力学的反应在此类法规中起着重要作用。体内研究表明，分支点中的EC表达了促动脉粥样硬化的表型。相比之下，动脉树的直部分中的EC是 暴露于高剪切流的情况下，净向前方向很大，这些区域通常免于动脉粥样硬化。 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自适应重塑。相反，没有明显的正向方向的振荡性剪切应力（OS）通过激活促增强，促氧化和促炎性基因而具有动脉粥样硬化。我们假设这一点，尽管PS和OS可能会在初始阶段激活类似的信号事件，但结果会随着时间而差异。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的差异功能后果。在这个拟议的项目中，我们将随着时间的推移在PS和OS下的ECS的信号传导，转录法规和功能表型。在这些流条件下绘制差异途径需要使用系统生物学方法，该方法为压力的差异响应提供了全面的机械和网络观点。为了系统地映射EC函数的流量调节，我们提出以下特定目的：（1）在PS vs vs，OS下建立EC信号事件的时间映射。 （2）研究在PS Vs vs，OS下的EC基因表达的转录法规。 （3）检查在PS vs，OS下，EC的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函数。 （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，以获取系统生物学分析所需的数据，以构建EC分子事件的生理和病理法规的分子和途径模型以及功能后果。这种综合和协作系统生物学方法将对机械传输的复杂过程产生新的见解，通过该过程，不同的流动模式通过该过程调节动脉壁中的稳态。这些发现将大大增强我们对动脉粥样硬化的分子和机械碱基的理解，动脉粥样硬化是心血管疾病中的主要病理生理事件。 公共卫生相关性：我们建议使用结合实验程序和生物信息学分析的系统生物学方法，以了解血管功能的血液动力学调节。最终的机理和途径模型将提供有关动脉粥样硬化机制的关键信息，这是一种主要的血管疾病，损害了心血管健康。该研究还将为疾病预防，治疗和管理提供新的知识。