Collaborative Research: The Effects of Extracellular Matrix Alignment on Cellular Mechanotransduction in 3D Architectures

合作研究：细胞外基质排列对 3D 架构中细胞力转导的影响

• 批准号: 1462710
• 负责人: Christopher Chen
• 金额: $ 30万
• 依托单位: Trustees of Boston University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1462710&HistoricalAwards=false
• 关键词: Collaborative; Research; Effects; Extracellular; Matrix

Cells in living organisms reside in a meshwork of protein fibers and other molecules, termed the extracellular matrix, which provides both structural support and chemical inputs that are critical to the functioning of the cells. The structural properties of the extracellular matrix are largely determined by how these protein fibers are aligned and organized, and changes in these structures and are associated with the progression of many human diseases, but in ways that in many cases are still not well understood. This award supports fundamental research that will provide needed insights into how the organization and resulting mechanical properties of the extracellular matrix influence and control both the normal and pathological behavior of cells. This research is relevant to ongoing efforts to develop methods to speed wound healing, and to engineer artificial tissues to repair damaged organs, and so the results from this work will have broad impact and provide critical resources to the biomedical community. This collaborative research program involves techniques and insights drawn from several fields, including bioengineering, physics, microfabrication, and cell biology, and provides interdisciplinary training needed to prepare the next generation of scientists and engineers.The adhesion of cells to the extracellular matrix plays a major role in many critical cellular functions important to embryonic development, adult tissue homeostasis, and disease pathogenesis, including cell survival, migration, proliferation, and differentiation. Yet, there have been few systems that allow control and therefore study the specific effects of fibrillar extracellular matrix architecture on cell function. This project use engineered microtissues to address the key hypothesis that alterations in the alignment of matrix, contractile activity of resident cells, geometry of boundary constraints, and external mechanical forces are highly coupled in a mechanotransduction machinery that will drive changes in cellular phenotype. These studies will determine how these factors regulate the transition of fibroblasts to an activated, fibrotic phenotype that is critical in wound healing as well as chronic fibrosis and scarring, but will apply more broadly to many cell types that response to mechanoadhesive cues.

活生物体中的细胞存在于蛋白质纤维和其他分子的网状结构中，称为细胞外基质，其提供对细胞功能至关重要的结构支持和化学输入。细胞外基质的结构特性在很大程度上取决于这些蛋白质纤维如何排列和组织，以及这些结构的变化，并与许多人类疾病的进展有关，但在许多情况下，这些结构的变化仍没有得到很好的理解。 该奖项支持基础研究，将提供所需的见解如何组织和细胞外基质的机械性能的影响和控制细胞的正常和病理行为。 这项研究与正在进行的开发加速伤口愈合方法的努力有关，并设计人工组织来修复受损器官，因此这项工作的结果将产生广泛的影响，并为生物医学界提供关键资源。 该合作研究计划涉及多个领域的技术和见解，包括生物工程，物理学，微细加工和细胞生物学，并提供跨学科的培训，为下一代科学家和工程师做好准备。细胞与细胞外基质的粘附在胚胎发育，成人组织稳态和疾病发病机制等许多关键细胞功能中起着重要作用，包括细胞存活、迁移、增殖和分化。然而，有几个系统，允许控制，因此研究纤维状细胞外基质结构对细胞功能的具体影响。该项目使用工程微组织来解决关键假设，即基质排列，驻留细胞的收缩活动，边界约束的几何形状和外部机械力的改变在机械转导机制中高度耦合，这将驱动细胞表型的变化。 这些研究将确定这些因子如何调节成纤维细胞向活化的纤维化表型的转变，这在伤口愈合以及慢性纤维化和瘢痕形成中至关重要，但将更广泛地应用于对机械粘附线索作出反应的许多细胞类型。