Synthetic 3D Model of the Carotid Artery to Study Exercise-Induced Changes in Endothelial Gene Expression

用于研究运动引起的内皮基因表达变化的颈动脉合成 3D 模型

• 批准号: 10801834
• 负责人: Alvaro N Gurovich
• 金额: $ 1.11万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-17 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10801834
• 关键词: 3-Dimensional; 3D Print; Actins; Aerobic Exercise; Affect; Age; Anatomy; Applications Grants; Area; Atherosclerosis; Biochemical; Biocompatible Materials; Biological Availability; Biomechanics; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cell Line; Cells; Characteristics; Clinical; Clinical Markers; Collagen; Computer Models; Cultured Cells; Data; Digital Imaging and Communications in Medicine; Down-Regulation; Elasticity; Endothelial Cells; Endothelin-1; Endothelium; Epigenetic Process; Epoprostenol; Exercise; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Glycocalyx; Health Professional; Homeostasis; Human; Hypertension; Image; Immunohistochemistry; In Vitro; Inflammatory; Intercellular adhesion molecule 1; Laboratories; Length; Magnetic Resonance Imaging; Mechanics; Medicine; Messenger RNA; Modeling; Molecular; Nitric Oxide; Nurses; Obesity; Oxidative Stress; Pathway interactions; Patients; Pattern; Physiological; Polymerase Chain Reaction; Printing; Process; Property; Proteins; Rehabilitation therapy; Reporting; Research; Rest; Reverse Transcription; Shapes; Stress; Stress Fibers; Stroke; Structural Protein; Surface; Technology; Testing; Tunica Intima; Vascular Cell Adhesion Molecule-1; Western Blotting; alpha Actinin; bioprinting; cardiovascular health; cardiovascular risk factor; cerebrovascular; endothelial dysfunction; exercise intensity; exercise physiologist; exercise program; experimental study; hemodynamics; heparin proteoglycan; human model; hypercholesterolemia; imaging study; improved; in vivo; mechanotransduction; personalized medicine; physical therapist; programs; protective factors; protein expression; receptor; shear stress; standard care; stressor; stroke survivor; three-dimensional modeling; transcription factor; translational approach; transmission process

Summary Approximately nine out of 10 cerebrovascular attacks are due to atherosclerosis. Additionally, endothelial dysfunction is currently accepted as the first pathophysiological step toward atherosclerosis. Endothelial cell homeostasis and gene expression is highly regulated via shear stress, which is directly associated with blood flow changes. Aerobic exercise (AX) has been associated with improved cardiovascular (CV) health. However, only ~50% of the beneficial effects of AX are explained via improvements on traditional CV risk factors (e.g., hypertension, hypercholesterolemia, obesity). The remainder ~50% of the beneficial effects of AX are unknown. Moreover, traditionally controlled AX does not provide personalized medicine, which could account for a high number of non-responders. Therefore, the main purpose of this proposal is to develop a 3D synthetic model of the human carotid artery using 3D bio-printing technology to simulate in vivo personalized AX-induced blood flow patterns and endothelial shear stress and to determine gene expression/transcription and molecular changes in endothelial cultured cells in vitro. Based on previous reports and our preliminary data we hypothesize that a 3D synthetic model of the carotid artery will respond to exercise-induced blood flow patterns as a normal carotid artery. In addition, we hypothesize that endothelial cultured cells under similar blood flow patterns and shear stress will increase the expression of atherosclerosis-protective mRNA/proteins (e.g., eNOS, PGI2, and SOD) and structural mRNA/proteins (e.g., actin, heparin sulfate proteoglycan [glycocalyx], and α-actinin-bundled stress fibers), and a decrease of pro- atherosclerosis and pro-inflammatory mRNA/protein expression (e.g., ICAM-1, VCAM-1, and ET-1) in a similar intensity-dependent manner. First, we will determine biomechanical properties (e.g., vessel distensibility and compliance) of the carotid artery in vivo during resting conditions and at 3 AX intensities in healthy, young subjects, patients with stroke, and age-matched controls. Then, subjects will undergo a magnetic resonance imaging (MRI) study to determine the exact shape (e.g., length and contour) of same tested carotid artery and the images will be used to build a 3D synthetic model via 3D bio-printing. The 3D synthetic model will mimic more anatomical and hemodynamic conditions, which will allow for more physiological in vitro experiments. Secondly, we will perform several flow patterns in endothelial cultured cells seeded on the 3D synthetic model. Flow patterns will be similar to those patterns observed during in vivo studies. After applying the different flow patterns, cells will be collected and processed to determine changes in specific gene transcription factors and protein expression. By characterizing blood flow patterns during different intensities of AX and determining the gene expression/transcription and molecular changes in endothelial cells under these same blood flow patterns, using a ‘reverse’ translation approach, we will explain the mechanisms of the cardiovascular protective factors associated with AX as personalized medicine, especially in stroke survivors.

总结