Intercadherin Interactions in Epithelial Cells

描述(申请人提供)：钙粘附素介导的黏附导致高度组织的黏附连接的形成，这是各种形态发生过程的关键结构。我们的实验表明，钙粘附素介导的黏附是建立在钙粘素黏附二聚体形成和解体之间的平衡的基础上的。这些动态是由一个活跃的过程介导的，该过程不断地从连接处移除钙粘附素分子。我们认为，这两个过程-钙粘蛋白二聚体组装和拆卸-控制细胞间接触的强度和可塑性。我们的资助围绕两个主题：钙粘附素粘附性二聚体聚集的机制和粘附性连接中钙粘附素的动力学机制。我们的初步实验表明，钙粘蛋白聚集是一个扩散陷阱过程，它受到多种机制的负调控，其中之一是钙粘蛋白内吞作用。在特定的目标1中，阐述了在非洲爪哇早期胚胎发育和人类角质形成细胞层化过程中调节钙粘蛋白聚集的确切机制以及这些机制在皮肤发育过程中的功能意义。2.在特定的目标2中阐明了粘附性连接中钙粘附素动力学的详细参数和分子方面。最后，可以调节钙粘附素动力学的钙粘附素/连环蛋白复合体的构象变化是特殊目标3的重点。该项目的完成将使我们能够设计特定的动物实验和临床研究，旨在了解钙粘附素黏附在伤口愈合、淋巴细胞和表皮渗透等复杂的正常和病理过程中的作用。这项工作也是朝着合成黏附调节剂的发展及其在医学上的应用迈出的关键一步。 与公共健康相关：我们的初步研究表明，钙粘素二聚体的组装和分解两个过程控制着细胞间接触的强度和可塑性。这项提案中设计的实验将揭示这两个关键过程的详细机制。这项研究的完成将使我们能够设计动物实验和临床研究，旨在了解钙粘附素在伤口愈合和病理形态发生中的作用，如淋巴细胞表皮渗透。这项工作将在其他领域产生重大影响，因为钙粘附素是组织几乎所有人体组织的基本过程。这项研究也是开发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.