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：
10227997
负责人：
ANDREW P. KOWALCZYK
金额：
$ 48.04万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227997
关键词：
Ablation Actins Address Adhesions Adhesives 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 Endothelium Enzymes Event Exposure to 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 Mutate Pathologic Pathway interactions Pattern Play Process Proteins Psoriasis Recycling Regulation Role Series Signal Transduction Skin Substrate Specificity Tail Tissues Ubiquitination Vascular Permeabilities Work angiogenesis base cadherin 5 cell motility design experimental study human disease insight malformation migration mouse genetics neovascularization new therapeutic target novel prevent skin disorder therapeutic target trafficking tumor tumorigenesis ubiquitin ligase ubiquitin-protein ligase vessel regression wound healing

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以皮肤病为特征的皮肤病中起着核心作用由表皮过度增殖或炎症引起。许多这些疾病的特点是增加血管通透性下降，导致皮肤水肿和病情恶化。此外，血管组织改变和/或新血管形成与牛皮癣、皮肤病有关肿瘤发生以及伤口愈合过程中的组织重塑。之间的粘合剂相互作用邻近的内皮细胞在血管通透性和重组中起着核心作用和血管生成过程中内皮细胞的生长。 VE-钙粘蛋白是一种细胞表面粘附分子内皮细胞特异性，在内皮生长控制、血管屏障中发挥着至关重要的作用功能以及与血管生成相关的形态发生事件。 VE-的胞外结构域钙粘蛋白介导细胞与细胞的接触，而 VE-钙粘蛋白的细胞质尾部结合一系列称为连环蛋白的蛋白质，将 VE-钙粘蛋白与肌动蛋白偶联并调节 VE-钙粘蛋白粘附。我们的研究表明，p120-连环蛋白是 VE-钙粘蛋白结合伴侣，与钙粘蛋白结合尾并防止 VE-钙粘蛋白内吞和降解。此外，有条件的基因消融实验表明，内皮细胞 p120-catenin 的缺失会导致血管畸形和发育过程中出血。最近，我们发现 E3 泛素连接酶靶向 VE-钙粘蛋白内吞作用和降解。因此，钙粘蛋白内吞作用受到高度调节，并且似乎对于血管模式和功能很重要。在这里，我们将探讨两种不同的功能我们最近发现了 VE-钙粘蛋白尾部的内吞信号。我们假设 VE-cad 内吞作用赋予内皮细胞极性和迁移所必需的粘附可塑性在正常血管发育过程中，泛素连接酶会导致异常的 VE-cad 内吞作用和退化。目标 1 研究将在细胞培养和小鼠中使用一系列方法确定 VE-钙粘蛋白内吞作用如何调节内皮细胞极性的遗传模型迁移，以及这些过程如何促进正常血管发育。目标 2 研究将重点关注卡波西肉瘤内皮肿瘤中表达的 MARCH 家族 E3 泛素连接酶。此外，我们将鉴定在内皮细胞中表达的内源性 MARCH 家族 E3 连接酶。细胞，并靶向 VE-钙粘蛋白，使其在发育和皮肤疾病期间降解。完成这些研究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的血管消退的可能治疗目标。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Different mechanisms regulate lysophosphatidic acid (LPA)-dependent versus phorbol ester-dependent internalization of the LPA1 receptor.

不同的机制调节 LPA1 受体的溶血磷脂酸 (LPA) 依赖性与佛波酯依赖性内化。

DOI：
发表时间：
2008-02-29
期刊：
影响因子：
0
作者：
Urs, Nikhil M;Kowalczyk, Andrew P;Radhakrishna, Harish
通讯作者：
Radhakrishna, Harish

Anthrax toxin receptor 1/tumor endothelium marker 8 mediates cell spreading by coupling extracellular ligands to the actin cytoskeleton.

炭疽毒素受体 1/肿瘤内皮标记物 8 通过将细胞外配体与肌动蛋白细胞骨架偶联来介导细胞扩散。

DOI：
发表时间：
2006-08-11
期刊：
影响因子：
0
作者：
Werner, Erica;Kowalczyk, Andrew P;Faundez, Victor
通讯作者：
Faundez, Victor

Endothelial Poldip2 regulates sepsis-induced lung injury via Rho pathway activation.

内皮 Poldip2 通过 Rho 通路激活调节脓毒症引起的肺损伤。

DOI：
10.1093/cvr/cvab295
发表时间：
2021-09-16
期刊：
Cardiovascular research
影响因子：
10.8
作者：
E. Dolmatova;Steven J Forrester;Keke Wang;Ziwei Ou;H. Williams;Giji Joseph;S;eep Kumar;eep;A. Valdivia;A. Kowalczyk;Hongyan Qu;H. Jo;B. Lassègue;M. S. Hern;es;es;K. Griendling
通讯作者：
K. Griendling

p120-Catenin regulates leukocyte transmigration through an effect on VE-cadherin phosphorylation.

p120-Catenin 通过影响 VE-钙粘蛋白磷酸化来调节白细胞迁移。

DOI：
10.1182/blood-2008-03-147181
发表时间：
2008-10-01
期刊：
Blood
影响因子：
20.3
作者：
P. Alcaide;G. Newton;S. Auerbach;Seema Sehrawat;T. Mayadas;D. Golan;P. Yacono;P. Vincent;A. Kowalc
通讯作者：
A. Kowalc

p120-catenin inhibits VE-cadherin internalization through a Rho-independent mechanism.

p120-连环蛋白通过 Rho 独立机制抑制 VE-钙粘蛋白内化。