Cadherin regulation in dermal endothelial cells

真皮内皮细胞中钙粘蛋白的调节

基本信息

批准号：
8185601
负责人：
ANDREW P. KOWALCZYK
金额：
$ 41.63万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8185601
关键词：
Ablation Actin-Binding Protein Actins Address Adherens Junction Adhesions Adhesives Animals Binding Binding Sites Blood Vessels Cadherins Cell Adhesion Molecules Cell Proliferation Cell physiology Cell surface Cell-Cell Adhesion Cells Chronic Disease Clathrin Clathrin Adaptors Complex Cues Cutaneous Cytoplasmic Tail Defect Dermal Development Disease Dissociation Down-Regulation Edema Endocytosis Endothelial Cells Event Extracellular Domain Family Family Dasypodidae Funding Gene Family Genes Genetic Models Growth Guanosine Triphosphate Phosphohydrolases Hemangioma Hemorrhage In Vitro Inflammation Intercellular Junctions Kaposi Sarcoma Link Maintenance Masks Mediating Microcirculation Modification Molecular Morphogenesis Mus Organ Pathway interactions Pattern Phenotype Play Proteins Psoriasis Regulation Research Design Role Series Signal Transduction Skin Surface System Tail Testing Tissues Ubiquitination Vascular Permeabilities Vimentin Wound Healing angiogenesis base cadherin 5 cell motility in vivo insight malformation member mouse model neovascularization new therapeutic target prevent research study rho rho GTP-Binding Proteins scaffold skin disorder therapeutic target tumor tumorigenesis ubiquitin-protein ligase vessel regression

项目摘要

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. PUBLIC HEALTH RELEVANCE: These studies are designed to generate new insights into the basic cellular mechanisms that regulate cell-cell adhesion, and to expose new therapeutic targets for the treatment of skin diseases characterized by alterations in vascular function and inflammation.

描述（由申请人提供）：皮肤微循环在一系列以表皮过度增殖或皮肤炎症为特征的皮肤疾病中起着核心作用。许多这些疾病的特征是血管通透性增加，导致皮肤水肿和疾病恶化。此外，改变的血管组织和/或新血管形成与牛皮癣、皮肤肿瘤发生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粘附相互作用在血管通透性以及血管生成过程中内皮细胞的重组和生长中发挥着核心作用。 VE-钙粘蛋白是一种内皮细胞特异性的细胞表面粘附分子，在内皮生长控制、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着至关重要的作用。 VE-钙粘蛋白的胞外结构域介导细胞与细胞的接触，而VE-钙粘蛋白的细胞质尾部充当一系列称为连环蛋白的蛋白质的支架，其将VE-钙粘蛋白与肌动蛋白和波形蛋白细胞骨架网络偶联。 p120 连环蛋白对 VE-钙粘蛋白的调节是本提案的重点。 p120-连环蛋白调节VE-钙粘蛋白的内吞作用和降解，条件基因消融实验表明，内皮p120-连环蛋白的缺失会导致发育过程中的血管畸形和出血。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。该提案的中心假设是 p120 和 VE-钙粘蛋白形成对血管发育至关重要的功能单元。此外，我们假设 p120 通过不同的分子机制调节钙粘蛋白内吞作用和粘附强度，从而通过不同的细胞途径促进内皮功能的不同方面。这些假设将通过结合体外和体内方法来确定 p120 对 VE-钙粘蛋白内吞作用、粘附强化机制以及内皮小管形成和增殖的贡献来解决。这些研究的完成将增进我们对基于钙粘蛋白的粘附机制的理解，并揭示调节血管生成和不适当血管消退的可能治疗靶点。公共健康相关性：这些研究旨在对调节细胞间粘附的基本细胞机制产生新的见解，并揭示治疗以血管功能和炎症改变为特征的皮肤病的新治疗靶点。