Intercadherin Interactions in Epithelial Cells

描述（由申请人提供）：钙粘蛋白介导的粘附导致形成高度组织化的粘附连接，这是各种形态发生过程的关键结构。我们的实验表明，钙粘蛋白介导的粘附是基于钙粘蛋白二聚体形成和分解之间的平衡。这些动力学是由一个主动过程介导的，该过程不断地从连接处移除钙粘蛋白分子。我们认为钙粘蛋白二聚体的组装和拆卸这两个过程控制着细胞间接触的强度和可塑性。我们的资助主要围绕两个主题：钙粘蛋白粘附二聚体聚集的机制和钙粘蛋白粘附连接的动力学机制。我们的初步实验表明，钙粘蛋白聚集是一个扩散陷阱过程，受到多种机制的负调控，其中一种机制是钙粘蛋白内吞作用。本文阐述了钙粘蛋白聚集的确切调控机制，以及这些机制在爪蟾早期胚胎发育和人类角质细胞分层过程中的功能意义。详细的参数和分子方面的阐明粘着连接钙粘蛋白动力学描述在具体目标2。最后，cadherin/catenin复合物的构象变化可能调节cadherin动力学是Specific Aim 3的重点。该项目的完成将使我们能够设计专门的动物实验和临床研究，旨在了解钙粘蛋白粘附在伤口愈合和淋巴细胞表皮浸润等复杂的正常和病理过程中的作用。这项工作也是合成黏附调节剂及其在医学上应用的关键一步。

DESCRIPTION (provided by applicant): Cadherin-mediated adhesion results in the formation of highly organized adherens junctions, the key structures for a variety of morphogenetic processes. Our experiments show that cadherin-mediated adhesion is based on the equilibrium between formation and disintegration of cadherin adhesive dimers. These dynamics are mediated by an active process that continuously removes cadherin molecules from the junction. We propose that these two processes-cadherin dimer assembly and disassembly- control the strength and plasticity of intercellular contacts. Our grant centers around two topics: the mechanisms of cadherin adhesive dimer clustering and the mechanisms of cadherin dynamics in adherens junctions. Our preliminary experiments suggest that cadherin clustering is a diffusion-trap process that is negatively regulated by diverse mechanisms, one of which is cadherin endocytosis. The exact mechanisms regulating cadherin clustering and the functional significance of these mechanisms during skin development in early Xenopus embryogenesis and human keratinocyte stratification are addressed in Specific Aim 1. The elucidation of the detailed parameters and molecular aspects of cadherin dynamics in adherens junctions is described in Specific Aim 2. Finally, the conformational changes in the cadherin/catenin complex that could regulate cadherin dynamics are the focus of Specific Aim 3. The completion of this project will allow us to design specific animal experiments and clinical studies aimed at understanding the role of cadherin adhesion in complex normal and pathological processes such as wound healing and lymphocyte epidermal infiltration. The proposed work is also a critical step toward the development of synthetic adhesion modulators and their application in medicine. PUBLIC HEALTH RELEVANCE: Our preliminary studies show that two processes-cadherin dimer assembly and disassembly- control the strength and plasticity of intercellular contacts. Experiments designed in this proposal will uncover detailed mechanisms of these two crucial processes. The completion of this research will allow us to design animal experiments and clinical studies aimed at understanding the role of cadherin adhesion in wound healing and pathological morphogenesis, such as lymphocyte epidermal infiltration. The work will make a significant impact in other fields, because cadherin adhesion is a basic process that organizes virtually all human tissues. The study is also a critical step toward the development of synthetic adhesion modulators and their application in medicine.