Endothelial cell response to disturbed flow in diabetic conditions

描述(申请人提供)：糖尿病患者会经历严重、加速的动脉粥样硬化，这会导致心脏病发作和中风。血糖控制可延缓糖尿病血管并发症，提示血糖是糖尿病心血管疾病的主要危险因素。然而，即使在糖尿病患者中，动脉分叉或弯曲的区域仍会形成动脉粥样硬化斑块。这表明，这些部位的血流变化与低血糖或高血糖结合在一起，会导致糖尿病动脉粥样硬化。血管内皮细胞排列在体内所有与血液接触的表面。健康的内皮细胞可以预防 通过控制血管通透性和炎症形成动脉粥样硬化斑块。在血流紊乱和血糖改变的情况下，内皮细胞功能紊乱，并促进动脉粥样硬化斑块的发展。虽然已经对这两种情况分别进行了研究，但糖化改变促进血流紊乱区域动脉粥样硬化斑块发展的机制尚未被研究。我们的研究目标是调查血糖和血流力学的改变如何相互作用，导致糖尿病患者动脉粥样硬化加速。我们之前的研究表明，低糖和高糖条件会改变内皮细胞对正常血流的反应方式。在这项建议中，我们的目标是研究低成本和 在血流正常或紊乱的情况下，高糖对内皮细胞的影响。我们假设，正常的血流保护内皮细胞免受葡萄糖诱导的损伤，但急性的葡萄糖变化加剧了紊乱的血流效应。我们将通过合作教育机会，让研究生和本科生参与研究。项目的成功完成将阐明正常的血流如何保护内皮细胞，而紊乱的血流如何加剧细胞损伤。这将提高我们对糖尿病动脉粥样硬化如何在全身性血糖变化的情况下仍然是一种局灶性疾病的理解。在未来，这将为糖尿病血管疾病创造新的治疗方法。通过在我们的细胞机械传递实验室提供6个月的合作教育职位，该项目还将为机械和生物医学工程本科生提供更多的研究机会。这些经历将扩大学生对生物力学研究多样性的认识，同时激励他们探索健康研究事业。

DESCRIPTION (provided by applicant): People with diabetes experience severe, accelerated atherosclerosis, which leads to heart attack and stroke. Blood sugar control delays diabetic vascular complications, suggesting that blood sugar is a primary risk factor for diabetic cardiovascular disease. However, even in people with diabetes, atherosclerotic plaques still develop in regions where arteries divide or bend. This suggests that blood flow changes at these locations combine with low or high blood sugar to cause diabetic atherosclerosis. Endothelial cells line all blood contacting surfaces in the body. Healthy endothelial cells prevent atherosclerotic plaque formation by controlling blood vessel permeability and inflammation. In both disturbed flow and altered glucose, endothelial cells are dysfunctional and promote atherosclerotic plaque development. While these two conditions have been studied individually, the mechanism by which altered glucose increases atherosclerotic plaque development in disturbed blood flow regions has not yet been studied. Our research goal is to investigate how altered blood sugar and blood flow mechanics interact to cause accelerated atherosclerosis in diabetes. We previously showed that low and high glucose conditions change the way that endothelial cells respond to normal blood flow. In this proposal, our objective is to study low and high glucose effects on endothelial cells in normal or disturbed blood flow. We hypothesize that normal blood flow protects endothelial cells from glucose-induced damage, but that acute glucose changes exacerbate disturbed flow effects. We will involve graduate and undergraduate students in the research through co-operative education opportunities. Successful project completion will clarify how normal blood flow protects endothelial cells and disturbed flow accentuates cell damage. This will improve our understanding of how diabetic atherosclerosis remains a focal disease despite systemic glucose changes. In the future, this will create new therapies for diabetic vascular disease. The will also enhance research opportunities for undergraduate mechanical and biomedical engineering students by providing 6 month co-operative education positions in our cellular mechanotransduction laboratory. These experiences will expand student awareness of biomechanics research diversity while inspiring them to explore health research careers.