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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：
9381479
负责人：
ANDREW P. KOWALCZYK
金额：
$ 47.9万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9381479
关键词：
Ablation Actins Address Adhesions Adhesives Alpha Cell Binding Binding Proteins Biological Blood Vessels Cadherins Capillary Permeability Cell Adhesion Cell Adhesion Molecules Cell Culture Techniques Cell Polarity Cell surface Cell-Cell Adhesion Cells Complex Cutaneous Cytoplasmic Tail Data Degradation Pathway Dermal Development Disease Dissociation Edema Endocytosis Endothelial Cells Enzymes Event Extracellular Domain Family Foundations Funding Gene Family Genes Genetic Models Genome Goals Growth Hemorrhage Herpesviridae Human Inflammation Inflammatory Kaposi Sarcoma Ligase Lysine Malignant Neoplasms Mediating Membrane Microcirculation Morphogenesis Mus Mutate Pathologic Pathway interactions Pattern Play Process Proteins Psoriasis Recycling Regulation Role Series Signal Transduction Skin Substrate Specificity Tail Tissues Ubiquitination Vascular Permeabilities Work Wound Healing angiogenesis base cadherin 5 cell motility design experimental study human disease insight malformation migration neovascularization new therapeutic target novel prevent skin disorder therapeutic target trafficking tumor tumorigenesis ubiquitin ligase ubiquitin-protein ligase vessel regression

项目摘要

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.

皮肤微循环在一系列皮肤病中起着核心作用