Injury-Induced Epithelial Cell Detachment and Cell Migration

描述（由申请人提供）：在趋化过程中，旁分泌信号梯度调节白细胞向损伤、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。从对整个动物组织的研究来看，越来越明显的是，来自周围环境中物理结构（例如细胞，ECM）的接触引导对于将迁移细胞定向到目标非常重要。这表明，扩散趋化信号和允许的组织环境必须同时存在，以允许白细胞快速迁移以重建组织稳态。我们在斑马鱼伤口检测模型中使用活体成像的初步结果表明，伤口触发邻近上皮细胞重排，白细胞利用这些组织修饰迁移到伤口。这些初步发现支持了一种假设，即除了直接的体内白细胞趋化性外，旁分泌

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.