Injury-Induced Epithelial Cell Detachment and Cell Migration

描述（由申请方提供）：旁分泌信号梯度在趋化过程中调节白细胞向损伤、感染或肿瘤部位的募集。白细胞检测趋化信号的浓度梯度并迁移到源。从整个动物组织中的工作中越来越明显的是，来自周围环境中的物理结构（例如细胞、ECM）的接触引导对于将迁移细胞定向到其靶标是重要的。这表明，扩散性趋化信号和允许的组织环境必须到位，以允许快速白细胞迁移，以重建组织稳态。我们的初步结果，使用活体成像在斑马鱼伤口检测模型，表明创伤触发相邻的上皮细胞重排和白细胞利用这些组织的修改迁移到伤口。这些初步的发现支持了这样的假设，即除了体内直接的白细胞趋化性，旁分泌 来源于损伤部位的信号在周围组织结构中产生促进细胞迁移的结构变化。利用斑马鱼创伤模型，我们将解决以下目标：（1）创伤诱导的信号调节上皮结构;（2）上皮细胞重排的细胞自主机制;（3）上皮结构对白细胞迁移动力学的作用。除了组织结构的调节外，我们还将关注与炎症相关的信号通路。为了解决组织结构变化的细胞生物学基础，我们将分析细胞连接蛋白的时空动力学。最后，我们将通过分析抑制细胞重排后白细胞通过上皮迁移的动力学来确定细胞重排的生理相关性。完成后，这个建议将扩大我们对伤口反应的理解，包括对周围上皮结构的新修饰和对细胞迁移的影响。重要的是，定义组织结构变化对迁移的影响将导致我们对病理背景下细胞迁移的理解，如癌症转移。这些新的见解将可能导致新一代的治疗应用，将通过影响周围组织环境的渗透性来调节细胞迁移。

DESCRIPTION (provided by applicant): Paracrine signaling gradients regulate leukocyte recruitment to injury, infection or tumor sites during chemotaxis. Leukocytes detect concentration gradients of chemotactic signals and migrate to the source. It is becoming increasingly evident from work in whole animal tissues that contact guidance from physical structures within the surrounding environment (e.g. cells, ECM) is important to orient migrating cells towards their target. This suggests that both diffusive chemotactic signals and a permissive tissue environment must be in place to permit rapid leukocyte migration to reestablish tissue homeostasis. Our preliminary results, using intravital imaging in a Zebrafish wound detection model, demonstrate that wounding triggers adjacent epithelial cell rearrangements and that leukocytes utilize these tissue modifications for migration to the wound. These preliminary findings support the hypothesis that, in addition to direct leukocyte chemotaxis in vivo, paracrine signals derived from an injury site produce structural changes in surrounding tissue architecture that promote cell migration. Using the Zebrafish wounding model, we will address the following aims: (1) the wound-induced signals regulating epithelial architecture; (2) the cell-autonomous mechanisms of cell rearrangements in epithelia; and (3) the role of epithelial architecture on leukocyte migration kinetics. We will focus on signaling pathways that have been linked to inflammation in addition to the regulation of tissue architecture. To address the cell biological basis of tissue structural changes, we will analyze the spatiotemporal dynamics of cell junction proteins. Finally, we will determine the physiological relevance of cell rearrangement by analyzing the dynamics of leukocyte migration through epithelial upon inhibition of the cell rearrangement. Upon completion, this proposal will broaden our understanding of the wound response to include a novel modification to surrounding epithelial architecture and the effects on cell migration. Importantly, defining the effects of tissue structural changes on migration will led to advances in our understanding of cell migration in pathological contexts, such as cancer metastasis. These new insights will likely lead to a new generation of therapeutic applications that will modulate cell migration through affecting the permeability of the surrounding tissue environment.