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

职业：内皮细胞内的生化和生物力学相互作用 - 基底膜协同调节单元

• 批准号: 0846751
• 负责人: Alisa Clyne
• 金额: $ 40万
• 依托单位: Drexel University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0846751&HistoricalAwards=false
• 关键词: CAREER; Biochemical; Biomechanical; Interaction; within

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.

0846751一个。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起始事件，心血管疾病是美国死亡的主要原因。在健康血管中，内皮细胞在复杂的三维环境中调节血管功能。细胞动态地整合来自其顶端表面和基底膜的流动血液的生化和机械刺激。生化环境的破坏（如葡萄糖升高）和机械环境的干扰（如低剪切应力）会导致内皮细胞功能障碍和随后的心血管疾病。糖尿病患者在低剪切应力位置会加速动脉粥样硬化，这表明生物化学和生物力学可能通过共同的信号通路相互作用。该项目的研究目的是利用葡萄糖诱导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的综合生化（生长因子）和生物力学（剪切应力）相互作用。这项研究将在一个三维实验系统中进行，在这个实验系统中，剪切应力可以应用于内皮细胞群（微流体）或单细胞（介电泳装置）在确定的基底膜基质上。本研究将血管壁的生物化学与生物力学相结合。该项目将发展定量关系，描述生长因子如何在机械条件下被调节，基底膜特性如何被剪切应力和高葡萄糖改变，以及这些基底膜变化如何影响内皮细胞的机械反应。对综合三维血管生物学的理解将得到加强，这些新知识可用于开发降低心血管发病率和死亡率的靶向药物治疗。此外，这种细胞和细胞外基质的整合模型可以在不同的细胞类型中翻译，以提高各种体外研究的生理相关性。在美国，65%的糖尿病患者死于心血管疾病。随着糖尿病患病率和病程的上升，对心血管疾病和糖尿病病理生理的研究可以减轻这种预测的医疗负担。PI将把研究与教育项目结合起来，探索工程和生命科学领域当前面临的挑战，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以及代际指导，激励学生，特别是女性和代表性不足的少数民族探索工程职业。拓展项目将使用最迷人的工程系统之一——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。