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Hemodynamics: Heterogeneous Endothelial Gene Expression

血流动力学：异质内皮基因表达

基本信息

批准号：
7417802
负责人：
Peter Francis Davies
金额：
$ 43.87万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7417802
关键词：
Address Adhesions Adult Animals Antioxidants Aorta Area Arterial Fatty Streak Arteries Atherosclerosis Bioinformatics Biology Biomechanics Blood Blood Circulation Blood Platelets Blood Vessels Blood flow CD44 gene Cell Adhesion Cell Separation Cell Shape Cells Characteristics Cholesterol Classification Coagulation Process Collaborations Common carotid artery Complex Computer Simulation Condition Contralateral Cooperative Research and Development Agreement Cultured Cells Development Devices Disease Doctor of Philosophy Elements Endothelial Cells Endothelium Environment Equilibrium Estrogen Replacement Therapy Evaluation Event Exhibits Exposure to Family suidae Female Functional disorder Gender Gene Cluster Gene Expression Gene Expression Profile Gene Expression Profiling Gene Proteins Gene Silencing Gene Transfer Genes Genetic Transcription Genome Genomics Grant Heterogeneity Hormonal Hormones Human In Situ In Vitro Individual Inflammation Inflammatory Informatics Intervention Intramural Research Program Investigation Joints Knockout Mice Knowledge Laboratories Lead Length Lesion Link Liquid substance Literature Location Mammals Maps Measures Medical Methodology Modeling Molecular Molecular Profiling Numbers Outcome Oxidation-Reduction Pathology Pathway interactions Pattern Personal Satisfaction Phase Phenotype Physiological Physiology Predisposing Factor Predisposition Prevalence Proteins Proteomics Publications Publishing RNA Interference RNA amplification Radiologic Health Regulation Reporting Research Personnel Resistance Risk Risk Factors Role Sex Characteristics Signal Transduction Simulate Site Small Interfering RNA Stenosis Stimulus Stress Sus scrofa Technology Testing Therapeutic Intervention Thoracic aorta Time Tissue-Specific Gene Expression Transcriptional Activation Transitional Cell Trees United States Food and Drug Administration Up-Regulation Upper arm Work animal facility aortic arch athero susceptible atherogenesis atheroprotective cardiovascular risk factor carotid sinus cost follow-up hemodynamics human disease hypercholesterolemia in vitro Model in vivo insight interest knock-down male mature animal neglect prevent programs protein expression research study response shear stress therapeutic target tissue culture tool

项目摘要

The endothelium is well recognized as a mechanotranduction interface influencing vessel physiology and pathology. The prevalence of atherogenesis in regions associated with complex disturbed flows in vivo has long been recognized yet the factors that predispose such sites and potentiate preferential atherosclerosis there are poorly understood. We propose that hemodynamic forces determine the susceptibility to atherosclerosis by regulation of the regional phenotype of endothelium at such sites. Preliminary profiling studies in the normal adult porcine aorta using microarray have shown differences in endothelial gene expression between areas prone to develop atherosclerotic lesions (disturbed flow) and those areas that are typically spared. Project 5 will address the hypothesis that at lesion-susceptible locations, the endothelial phenotype is in an equilibrium state that is primed to develop atherosclerosis by expression of pro-inflammatory genes but is protected by the up-regulation of anti-oxidant mechanisms and other genes that prevent the initiation/early development of atherosclerosis. Exposure to one or more risk factors (additional to hemodynamics) is proposed to be necessary for imbalances that lead to the development of vascular pathology. In a collaboration with the Center for Devices and Radiological Health animal facility at the FDA Laurel, MD, we will conduct the first multi-gene expresssion studies of endothelium in vivo in defined hemodynamic locations. Regional endothelial phenotypes will be defined in normal adult porcine arteries, and the effects of the important risk factors hypercholesterolemia, gender, and hormonal manipulations upon atherosclerosis-primed regions will be determined. The critical role of hemodynamics in regional susceptibility will be tested by creating flow disturbances in the common carotid artery, a location that is normally exposed to undisturbed laminar flow and which is resistant to atherogenesis; we propose that a susceptible phenotype will result from such intervention. The effects of hemodynamic forces upon anti-oxidant, coagulation, inflammatory and other gene classifications will be measured in vitro where transcription profiles of porcine endothelial cells exposed to oscillating and unidirectional flow will be analyzed. Using small interfering RNA, specific gene 'knock-downs' will be created (gene silencing) to determine the effect upon hemodynamic responses in vitro including perturbations of the phenotype as evaluated by microarray profiling with follow-up protein and proteomic studies.

内皮被认为是影响血管生理和病理的机械传导界面。动脉粥样硬化在体内复杂紊乱血流相关区域的患病率早已被认识到，但对这些部位的易感性和潜在的优先动脉粥样硬化的因素知之甚少。我们提出，血流动力学力量通过调节这些部位的内皮细胞的区域表型来决定对动脉粥样硬化的易感性。在正常成年猪主动脉中使用微阵列进行的初步分析研究显示了不同区域内皮基因表达的差异