Cadherin regulation in dermal endothelial cells

真皮内皮细胞中钙粘蛋白的调节

• 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
• 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

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生或皮肤炎症为特征的皮肤疾病中起着核心作用。这些疾病中的许多以血管渗透性增加为代表，导致皮肤水肿和疾病恶化。此外，改变的血管组织和/或新血管形成与银屑病、皮肤肿瘤发生和伤口愈合期间的组织重塑相关。相邻内皮细胞之间的粘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重要作用。VE-钙粘蛋白是内皮细胞特异性的细胞表面粘附分子，其在内皮生长控制、血管屏障功能和与血管生成相关的形态发生事件中起关键作用。VE-钙粘蛋白的胞外结构域介导细胞与细胞的接触，而VE-钙粘蛋白的胞质尾区作为一系列称为连环蛋白的蛋白质的支架发挥作用，连环蛋白将VE-钙粘蛋白偶联到肌动蛋白和波形蛋白细胞骨架网络。p120连环蛋白对VE-钙粘蛋白的调控是本提案的重点。p120- catenin调节VE-钙粘蛋白的内吞和降解，条件性基因消融实验表明内皮p120-catenin的缺失导致发育过程中的血管畸形和出血。然而，p120的损失损害微血管图案和血管完整性的机制尚未完全了解。该提议的中心假设是p120和VE-钙粘蛋白形成了一个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的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。这些假设将使用体外和体内方法的组合来确定p120对VE-钙粘蛋白内吞作用、粘附增强机制以及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粘附机制的理解，并揭示可能的治疗靶点，以调节血管生成和不适当的血管消退。 公共卫生相关性：这些研究旨在对调节细胞-细胞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。