Mechanotransduction in Multicellular Systems

项目摘要 组织结构的改变是许多发育、生理和病理的主要决定因素。 病理生理过程，往往涉及协调运动的群体的身体相互作用 这是一种称为集体细胞迁移的现象。这种现象在一个国家中有许多不同的形式。 多种过程，如胚胎发育、伤口愈合和癌症转移。理解 因此，集体细胞迁移的决定因素和调节因素对人类健康非常重要。 介导集体细胞迁移的关键过程被认为涉及力的产生， 细胞间的机械耦合，但基本的分子机制仍然知之甚少。的 这项工作的长期目标是了解调解集体的关键机械敏感机制， 细胞迁移为了实现这一目标，我们创造并验证了一套创新的技术， 分子尺度，集体迁移细胞内的机械敏感过程。具体来说，我们专注于 机械连接蛋白粘着斑蛋白，由于其调节力诱导的粘附强化的能力， 在承重组织发育中的既定作用，以及作为机械敏感性的新兴功能， 肿瘤进展的调节剂。本提案的总体目标是利用这些技术开发和 测试集体细胞迁移的新概念模型，其中领导细胞激活 在周围细胞中与长春新碱相关的机械敏感性通路， 迁移我们将确定1）集体迁移的细胞是否产生分子张力的空间梯度 2）力的空间变化导致机械敏感的差异激活， 信号传导，3）粘着斑蛋白负荷和粘着斑蛋白动力学之间的关系是空间组织的， 在集体细胞迁移过程中进行生物化学调节，以及4）细胞粘附结构稳定性决定 细胞集体迁移的形式。加强对这些过程的机械理解将 增加我们对组织结构调节的基本知识。因此，这些研究与 国家卫生研究院的使命，因为他们将导致在许多领域，包括癌症，出生缺陷，创伤， 愈合和组织再生。

PROJECT SUMMARY Tissue structure alterations are primary determinants of many developmental, physiological, and pathophysiological processes and often involve the coordinated movements of groups of physically interacting cells, a phenomenon referred to as collective cell migration. This phenomenon takes many different forms in a variety of processes such as embryonic development, wound healing, and cancer metastasis. Understanding the determinants and regulators of collective cell migration is therefore of great importance to human health. The critical processes mediating collective cell migration are thought to involve force generation and mechanical coupling among cells, but the underlying molecular mechanisms remain poorly understood. The long-term goal of this work is to understand the key mechanically-sensitive mechanisms mediating collective cell migration. Toward this goal, we have created and validated a set of innovative techniques for studying molecular scale, mechanically-sensitive processes within collectively migrating cells. Specifically, we focus on the mechanical linker protein vinculin, given its ability to regulate force-induced adhesion strengthening, established role in the development of load-bearing tissues, and emerging function as a mechanically-sensitive regulator of tumor progression. The overall objective of this proposal is to use these techniques to develop and test a novel conceptual model of collective cell migration in which forces generated by a leader cell activate vinculin-associated mechanosensitive pathways in surrounding cells to initiate coordinated directional migration. We will determine if 1) collectively migrating cells generate spatial gradients of molecular tension across vinculin, 2) spatial variations in force lead to the differential activation of mechanically sensitive signaling, 3) the relationship between vinculin load and vinculin dynamics is spatially organized and biochemically regulated during collective cell migration, and 4) cellular adhesion structure stability determines the form of collective cell migration. An enhanced mechanistic understanding of these processes would increase our fundamental knowledge of the regulation of tissue structure. Thus, these studies are relevant to the NIH's mission, as they will lead to new insights in many fields including cancer, birth defects, wound healing, and tissue regeneration.