Rapid micro-patterned stretching platform to study cell behaviors during atherosclerosis

快速微图案拉伸平台研究动脉粥样硬化期间的细胞行为

• 批准号: 9168026
• 负责人: Ryan Christopher Hayward
• 金额: $ 23.93万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9168026
• 关键词: Adhesives; Arteries; Atherosclerosis; Beds; Behavior; Binding; Biochemical; Biocompatible Materials; Biological Assay; Biological Models; Biomedical Engineering; Cardiovascular Agents; Cardiovascular Diseases; Cell Count; Cells; Characteristics; Chemicals; Chemistry; Communities; Couples; Cues; Deposition; Development; Devices; Disease Progression; Elasticity; Environment; Generations; Genetic Transcription; Grant; Growth; Heterogeneity; Hydrogels; Imaging Techniques; In Vitro; Individual; Inflammatory; Integrin Binding; Integrins; Mechanics; Methods; Modeling; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Population; Process; Proliferating; Property; Proteins; Public Health; Reporting; Signal Transduction; Smooth Muscle Myocytes; Stretching; Surface; Swelling; System; Technology; Temperature; Variant; abstracting; base; cell behavior; cell motility; chemical property; clinical application; cytokine; extracellular; improved; in vitro testing; in vivo; insight; novel; novel therapeutic intervention; physical property; response

Abstract The physical and biochemical components of the arterial microenvironment, such as matrix stiffness and elasticity, and the portfolio of insoluble adhesive proteins, are altered during atherosclerosis. Coincident with these extracellular changes, smooth muscle cells (SMCs) undergo phenotypic dedifferentiation, wherein they alter gene transcription, become motile, and proliferate. Chemical and physical cues from the growing plaque, as well as the remodeled matrix, trigger the invasion of SMCs into the arterial intimal wall via activation of integrin- and growth factor-initiated signaling networks. Once there, these pathophysiological SMCs proliferate and deposit proteins, participating in disease progression. This process is well documented and appreciated in vivo, and many lab, including our own, have sought to make a connection between these physical matrix changes and SMC patho-physiology. However, there remains a critical gap in the field, as existing model systems have likely been still far to simple to capture the complexity of this in vivo phenomenon. In response to this critical gap, we propose to adapt and improve our model system that has independent control over static mechanical properties (elastic modulus), dynamic mechanical forces (rate and magnitude of stretch), and integrin binding. This is a high-throughput device that will allow for rapid, simultaneous profiling of hundreds of individual cells as a function of several different vessel property conditions. As proof of concept toward possible clinical applications, we will quantify SMC response to cardiovascular drugs while subjected to physiological stiffness, integrin binding, and stretch. We propose this system could transform the field's view of how matrix mechanics in a diseased vessel wall alter SMC behavior, ultimately leading to new therapeutic approaches targeting SMC mechanosensing.

摘要 动脉微环境的物理和生化成分，例如基质硬度和 弹性和不溶性粘附蛋白质的组合在动脉粥样硬化期间改变。重合 在这些细胞外变化中，平滑肌细胞（SMC）经历表型去分化，其中它们 改变基因转录，变得能动，并增殖。从不断增长的牙菌斑中得到的化学和物理线索， 以及重塑的基质，通过激活平滑肌细胞， 整合素和生长因子启动的信号网络。一旦到达那里，这些病理生理性SMC就会增殖 和存款蛋白质，参与疾病的进展。这一过程在以下文件中得到了很好的记录和赞赏： vivo和许多实验室，包括我们自己实验室，都试图在这些物理矩阵之间建立联系 变化和SMC病理生理学。然而，由于现有模式， 系统可能仍然过于简单，无法捕捉这种体内现象的复杂性。 为了应对这一关键差距，我们建议调整和改进我们的模型系统， 对静态机械性能（弹性模量）、动态机械力（机械力的速率和大小）的控制 拉伸）和整合素结合。这是一个高通量的设备，将允许快速，同时分析 数百个单独的细胞作为几种不同血管特性条件的函数。作为概念证明 为了可能的临床应用，我们将量化SMC对心血管药物的反应，同时受到 生理硬度、整合素结合和拉伸。我们建议这个系统可以改变该领域的观点， 病变血管壁中的基质力学如何改变SMC行为，最终导致新的治疗方法 针对SMC机械传感的方法。