Cadherin Regulation in Dermal Endothelial Cells

皮肤微循环在一系列以皮肤为特征的疾病中起着中心作用。 由表皮过度增殖或炎症引起的。其中许多疾病的典型特征是 血管通透性，导致皮肤浮肿和疾病加重。此外, 血管组织改变和/或新生血管与银屑病、皮肤 肿瘤的发生和伤口愈合过程中的组织重塑。粘合剂之间的相互作用 邻近的内皮细胞在血管通透性和重组中都起着中心作用。 以及血管生成过程中内皮细胞的生长。VE-钙粘附素是一种细胞表面黏附分子 特异性的内皮细胞，在内皮生长控制、血管屏障中起着至关重要的作用 功能和与血管生成相关的形态发生事件。VE的胞外区- 钙粘蛋白介导细胞间的接触，而VE-钙粘蛋白的细胞质尾巴与一系列 被称为连接素的蛋白质将VE-钙粘附素与肌动蛋白偶联，并调节VE-钙粘附素的黏附。我们的 研究表明，p120-catenin是一种与钙粘蛋白结合的VE-钙粘蛋白结合伙伴 尾部，并防止VE-钙粘附素内吞和降解。此外，条件性基因消融 实验表明，内皮细胞p120-catenin的缺失会导致血管畸形和 发育过程中的出血。最近，我们发现E3泛素连接靶向VE-钙粘蛋白 内吞和降解。因此，钙粘附素内吞作用受到高度调控，似乎是 对血管构型和功能很重要。在这里，我们将探索两个不同的功能 VE-钙粘蛋白尾部的内吞信号，这是我们最近发现的。我们假设VE-cad 内吞作用赋予内皮细胞极化和迁移所必需的粘附性可塑性 在正常的血管发育过程中，泛素连接酶导致异常的VE-cad内吞 和退化。Aim 1的研究将在细胞培养和小鼠身上使用一系列方法 确定VE-钙粘附素内吞如何调节内皮细胞极性和 迁移，以及这些过程如何有助于正常的血管发育。AIM 2研究将 重点关注在Kaposi肉瘤内皮肿瘤中表达的3月家族E3泛素连接酶。 此外，我们还将鉴定内源性MARCH家族E3连接酶在内皮细胞中的表达 这些细胞以VE-钙粘附素为靶点，在发育和皮肤病期间降解。完成 这些研究将促进我们对基于钙粘附素的黏附机制的理解，并揭示 可能的治疗靶点，以调节血管生成和不适当的血管倒退。

The cutaneous microcirculation plays a central role in a range of skin diseases that are characterized by epidermal hyperproliferation or inflammation. Many of these diseases are typified by increased vascular permeability, which causes 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 and 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 binds to a series of proteins termed catenins, which couple VE-cadherin to actin and regulate VE-cadherin adhesion. Our work has shown that p120-catenin is a VE-cadherin binding partner that associates with the cadherin tail and prevents VE-cadherin endocytosis and degradation. Further, conditional gene ablation experiments showed that deletion of endothelial p120-catenin leads to vascular malformations and hemorrhage during development. Recently, we found that E3 ubiquitin ligases target VE-cadherin for endocytosis and degradation. Thus, cadherin endocytosis is highly regulated and appears to be important for vascular patterning and function. Here, we will explore the function of two different endocytic signals in the VE-cadherin tail that we have recently identified. We hypothesize that VE-cad endocytosis confers adhesive plasticity that is necessary for endothelial cell polarity and migration during normal vascular development, and that ubiquitin ligases cause aberrant VE-cad endocytosis and degradation. Aim 1 studies will use a series of approaches in both cell culture and in mouse genetic models to determine how VE-cadherin endocytosis regulates endothelial cell polarity and migration, and how these processes contribute to normal vascular development. Aim 2 studies will focus on a MARCH family E3 ubiquitin ligase expressed in Kaposi sarcoma endothelial tumors. Further, we will identify the endogenous MARCH family E3 ligases that are expressed in endothelial cells and which target VE-cadherin for degradation during development and skin disease. 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.