CAREER: Biochemical and Biomechanical Interaction within the Endothelial Cell - Basement Membrane Co-Regulatory Unit

0846751A。Morss-Clyne型内皮细胞损伤被认为是动脉粥样硬化斑块发展和心血管疾病的始动事件，在美国是导致死亡的主要原因。在健康的血管中，内皮细胞在复杂的三维环境中调节血管功能。细胞在其顶端表面和基底面的基底膜上动态地结合来自流动的血液的生化和机械刺激。生化环境的紊乱，如高血糖，以及机械环境的紊乱，如低切应力，都会导致内皮细胞功能障碍和随后的心血管疾病。糖尿病患者在低切应力部位发生动脉粥样硬化加速，提示生物化学和生物力学可能通过共同的信号通路相互作用。本项目的研究目的是利用葡萄糖诱导的内皮细胞和基底膜的改变来研究内皮细胞基底膜共调节单元内整合的生化(生长因子)和生物力学(剪应力)相互作用。这项研究将在一个三维实验系统中进行，在这个系统中，剪应力可以施加到定义的基底膜基质上的内皮细胞群(微流体)或单个细胞(介电泳仪)。这项研究整合了血管壁的生物化学和生物力学。该项目将建立定量关系，描述生长因子如何在机械条件下调节，基底膜特性如何因剪切力和高糖而改变，以及这些基底膜变化如何影响内皮细胞的机械反应。对集成的三维血管生物学的了解将得到加强，这一新知识随后可以用于开发降低心血管发病率和死亡率的有针对性的药物疗法。此外，这种细胞和细胞外基质的整合模型可以跨不同的细胞类型进行翻译，以提高各种体外研究的生理学相关性。在美国，心血管疾病占糖尿病患者死亡的65%。随着糖尿病患病率和病程的上升，对心血管疾病和糖尿病的病理生理学的研究可以减轻这一预期的医疗负担。PI将把研究与教育项目结合起来，探索工程学和生命科学相结合的当前挑战，并在学生、教师和社区之间建立联系。该项目的教育目标是通过提供生物医学发现机会和代际指导，激励学生，特别是妇女和代表性不足的少数群体，探索工程职业。推广项目将使用最吸引人的工程系统之一--人体，向来自不同背景的学生展示工程师如何帮助解决社会挑战。

0846751A. Morss-ClyneEndothelial cell injury is considered the initiating event in atherosclerotic plaque development and cardiovascular disease, the leading cause of mortality in the United States. In a healthy blood vessel, endothelial cells regulate vascular function in a complex three-dimensional environment. Cells dynamically integrate biochemical and mechanical stimulation from the flowing blood at their apical surface and the basement membrane at their basolateral surface. Disruptions in the biochemical environment, such as elevated glucose, and disturbances in the mechanical environment, such as low shear stress, contribute to endothelial cell dysfunction and subsequent cardiovascular disease. People with diabetes develop accelerated atherosclerosis at low shear stress locations, suggesting that biochemistry and biomechanics may interact through common signaling pathways.The research objective of this project is to use glucose-induced alterations in endothelial cells and basement membrane to investigate integrated biochemical (growth factor) and biomechanical (shear stress) interactions within the endothelial cell basement membrane co-regulatory unit. This research will be conducted in a three-dimensional experimental system, in which shear stress can be applied to endothelial cell populations (microfluidics) or single cells (dielectrophoretic device) on defined basement membrane substrates.This research integrates biochemistry and biomechanics in the vascular wall. The project will develop quantitative relationships describing how growth factors are regulated in mechanical conditions, how basement membrane properties are altered by shear stress and high glucose, and how these basement membrane changes affect the endothelial cell mechanical response. Understanding of integrated, three-dimensional vascular biology will be enhanced, and this new knowledge can then be used to develop targeted pharmaceutical therapies that decrease cardiovascular morbidity and mortality. Furthermore, this integrative model of cell and extracellular matrix can be translated across diverse cell types to improve the physiological relevance of a wide variety of in vitro studies. In the United States, cardiovascular disease accounts for 65% of deaths in people with diabetes. With diabetes prevalence and disease duration on the rise, research into the pathophysiology of cardiovascular disease and diabetes could alleviate this predicted healthcare burden.The PI will integrate research with educational programs that explore current challenges at the interface of engineering and life sciences and create connections among students, faculty, and the community. The educational objective of this project is to inspire students, especially women and underrepresented minorities, to explore engineering careers by providing biomedical discovery opportunities coupled with intergenerational mentoring. Outreach programs will use one of the most fascinating engineering systems, the human body, to demonstrate to students from diverse backgrounds how engineers can help solve societal challenges.