Vascular mechanobioengineering

心血管疾病是社会的一个重要负担。动脉粥样硬化斑块早在儿童时期就已经形成，并且已经确定了系统性的危险因素，以及潜在的预防和治疗途径。鉴于目前的大流行，努力的目标是通过生物标志物鉴定和分子成像开发进行诊断，并通过开发新分子进行治疗。**动脉粥样硬化是局部发生的，与内皮细胞的力学生物学有关。体外、离体和体内研究发现了动脉粥样硬化的特征，如炎症标志物的表达。动脉重构通过基质金属蛋白酶及其抑制剂的作用改变了血管壁的几何形状，以及细胞外基质的组成/取向，通过迁移、增殖和凋亡改变了细胞含量，潜在地影响了进展和结果。了解重塑对机械生物学的影响可以为早期检测和改进治疗提供新的靶点。**将在体外检测炎症标志物和基质金属蛋白酶的调节。主要目标是：(1)设计和验证体外机械刺激系统，(2)研究内皮细胞在均匀几何支架中暴露于壁剪切应力或循环应变下的炎症反应，以及(3)表征模拟动脉重构支架中内皮细胞在复杂机械刺激（血流动力学剪切和机械应变）下的反应。**开发的体外模型将为研究团体提供机械生物学研究工具，允许在其他细胞类型、药物制剂和其他病理情况下进行测试。确定的生物标志物将为制药行业提供潜在的新药物治疗，以及正在开发的分子成像探针的靶标。机械生物学研究将提供关于生物标志物的重要信息，最终导致预期寿命/质量的提高，并使个人受益，这反过来将对加拿大产生积极的社会和经济影响。******

Cardiovascular diseases represent an important burden for society. Atherosclerotic plaques develop as early as childhood and systemic risk factors have been identified, along with potential preventative and therapeutic avenues. Given the current pandemic, efforts are targeted towards diagnosis, through biomarker identification and molecular imaging development, and treatment, by developing novel molecules. ** Atherosclerosis develops focally and is linked to endothelial mechanobiology. In vitro, ex vivo and in vivo studies identified hallmarks of atherosclerosis such as expression of inflammatory markers. Arterial remodelling alters vessel wall geometry, as well as extracellular matrix composition/orientation, through the action of matrix metalloproteinases and their inhibitors, and cellular content, through migration, proliferation and apoptosis, potentially affecting progression and outcome. Understanding the effects of remodelling on mechanobiology can provide novel targets for earlier detection and improved treatments. ** Regulation of inflammatory markers and matrix metalloproteinases will be examined in vitro. The main objectives are to (1) design and validate in vitro systems for mechanical stimulation, (2) study inflammatory response of endothelial cells exposed to wall shear stress or cyclic strain in uniform geometry scaffolds, and (3) characterize endothelial cell response under complex mechanical stimuli (both hemodynamic shear and mechanical strain) in scaffolds mimicking remodelled arteries.** The developed in vitro models will provide tools to the research community for mechanobiological studies, allowing tests on other cell types, pharmaceutical agents and in other pathological contexts. The biomarkers identified will provide potential new drug therapies, of interest to the pharmaceutical industry, and targets for molecular imaging probes that are being developed. Mechanobiological studies will provide crucial information on biomarkers, eventually leading to increased life expectancy/quality and benefiting individuals which in turn will have both a positive social and economic effect on Canada.******