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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：
8536356
负责人：
SHU CHIEN
金额：
$ 101.78万
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/8536356
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.

描述（由申请人提供）：动脉粥样硬化病变的局灶性表明，血液动力学对健康和疾病中血管稳态的调节至关重要。血管内皮细胞（ECs）对血流动力学力的反应在这种调节中起着重要作用。体内研究表明，分支点的内皮细胞表达促动脉粥样硬化表型。相比之下，动脉树直段的ECs是