Cadherin regulation in dermal endothelial cells

描述（由申请人提供）：皮肤微循环在一系列以表皮增生或皮肤炎症为特征的皮肤病中起核心作用。许多这些疾病的典型特征是血管通透性增加，导致皮肤水肿和疾病恶化。此外，血管组织的改变和/或新生血管与牛皮癣、皮肤肿瘤发生和伤口愈合过程中的组织重塑有关。在血管生成过程中，相邻内皮细胞之间的粘附相互作用在血管通透性和内皮细胞的重组和生长中起着核心作用。VE-cadherin是内皮细胞特异性的细胞表面粘附分子，在内皮细胞生长控制、血管屏障功能和血管生成相关的形态发生事件中起着至关重要的作用。VE-钙粘蛋白的胞外结构域介导细胞间的接触，而VE-钙粘蛋白的细胞质尾部作为一系列被称为连环蛋白的蛋白质的支架，将VE-钙粘蛋白与肌动蛋白和静脉蛋白细胞骨架网络偶联。p120 catenin对VE-cadherin的调控是本课题的重点。p120-catenin调节VE-cadherin的内吞和降解，条件基因消融实验表明，内皮细胞p120-catenin的缺失会导致发育过程中血管畸形和出血。然而，p120缺失损害微血管模式和血管完整性的机制尚不完全清楚。该建议的中心假设是p120和ve -钙粘蛋白形成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蛋白的内吞作用和粘附强度，从而通过不同的细胞途径参与内皮功能的不同方面。这些假设将通过体外和体内方法的结合来解决，以确定p120对ve -钙粘蛋白内吞作用、粘附增强机制和内皮小管形成和增殖的贡献。这些研究的完成将促进我们对钙粘蛋白黏附机制的理解，并揭示可能的治疗靶点，以调节血管生成和不适当的血管退化。

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.