Cadherin regulation in dermal endothelial cells

描述(申请人提供)：皮肤微循环在以表皮过度增殖或皮肤炎症为特征的一系列皮肤病中起核心作用。其中许多疾病的典型特征是血管通透性增加，导致皮肤浮肿和疾病恶化。此外，改变的血管组织和/或新生血管与银屑病、皮肤肿瘤的形成以及伤口愈合过程中的组织重塑有关。相邻内皮细胞之间的黏附相互作用在血管通透性和血管生成过程中内皮细胞的重组和生长中起着核心作用。VE-钙粘附素是一种内皮细胞特有的细胞表面黏附分子，在内皮细胞生长控制、血管屏障功能以及与血管生成相关的形态发生事件中发挥重要作用。VE-cadherin的胞外结构域介导细胞间的接触，而VE-cadherin的胞浆尾巴作为一系列蛋白质的支架，这些蛋白质被称为连接素，将VE-cadherin连接到肌动蛋白和波形蛋白的细胞骨架网络。P120连环蛋白对VE-钙粘附素的调控是本研究的重点。P120-catenin调节VE-cadherin的内吞和降解，条件性基因消融实验表明，内皮p120-catenin的缺失会导致发育过程中的血管畸形和出血。然而，p120缺失对微血管构型和血管完整性的影响机制尚不完全清楚。这一提议的中心假设是p120和VE-钙粘附素形成了一个对血管发育至关重要的功能单位。此外，我们假设p120通过不同的分子机制调节钙粘附素的内吞作用和黏附强度，从而通过不同的细胞途径对内皮功能的不同方面做出贡献。这些假说将使用体外和体内相结合的方法来解决，以确定p120对VE-钙粘蛋白内吞作用的贡献，黏附加强机制，以及内皮管的形成和增殖。这些研究的完成将促进我们对基于钙粘附素的粘连机制的理解，并揭示调节血管生成和不适当的血管退缩的可能的治疗靶点。

DESCRIPTION (provided by applicant): The cutaneous microcirculation plays a central role in a range of skin diseases that are characterized by epidermal hyperproliferation or cutaneous inflammation. Many of these diseases are typified by increased vascular permeability, leading to cutaneous edema and exacerbation of disease. In addition, altered vascular organization and/or neovascularization are associated with psoriasis, skin tumorigenesis, and with tissue remodeling during wound healing. Adhesive interactions between adjacent endothelial cells play a central role in both vascular permeability and in the reorganization and growth of endothelial cells during angiogenesis. VE-cadherin is a cell surface adhesion molecule specific to endothelial cells which plays a crucial role in endothelial growth control, vascular barrier function and in morphogenic events associated with angiogenesis. The extracellular domain of VE- cadherin mediates cell to cell contact, whereas the cytoplasmic tail of VE-cadherin functions as a scaffold for a series of proteins termed catenins, which couple VE-cadherin to actin and vimentin cytoskeletal networks. p120 catenin regulation of VE-cadherin is the focus of this proposal. p120- catenin regulates VE-cadherin endocytosis and degradation, and conditional gene ablation experiments indicate that deletion of endothelial p120-catenin leads to vascular malformations and hemorrhage during development. However, the mechanism by which loss of p120 compromises microvascular patterning and vessel integrity is not fully understood. The central hypothesis of this proposal is that p120 and VE-cadherin form a functional unit that is critical for vascular development. Furthermore, we hypothesize that p120 regulates cadherin endocytosis and adhesion strength through distinct molecular mechanisms, and thereby contributes to different aspects of endothelial function through different cellular pathways. These hypotheses will be addressed using a combination of in vitro and in vivo approaches to determine the contribution of p120 to VE-cadherin endocytosis, adhesion strengthening mechanisms, and endothelial tubule formation and proliferation. Completion of these studies will advance our understanding of cadherin based adhesion mechanisms and reveal possible therapeutic targets to regulate angiogenesis and inappropriate vascular regression.