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:
    9752474
  • 负责人:
  • 金额:
    $ 47.9万
  • 依托单位:
  • 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

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疾病中起着核心作用, 表皮过度增生或炎症。其中许多疾病的典型症状是 血管渗透性,导致皮肤水肿和疾病恶化。此外,本发明还提供了一种方法, 改变的血管组织和/或新血管形成与银屑病、皮肤 肿瘤发生,并与伤口愈合过程中的组织重塑有关。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起着中心作用, 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 特异于内皮细胞,并在内皮生长控制、血管屏障 功能和与血管生成相关的形态发生事件。VE的胞外结构域 钙粘蛋白介导细胞与细胞的接触,而VE-钙粘蛋白的胞质尾区与一系列的 称为连环蛋白的蛋白质,其将VE-钙粘蛋白偶联到肌动蛋白并调节VE-钙粘蛋白粘附。我们 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,条件性基因切除 实验表明内皮p120-连环蛋白的缺失导致血管畸形, 在发育过程中出血。最近,我们发现E3泛素连接酶靶向VE-钙粘蛋白, 内吞和降解。因此,钙粘蛋白的内吞作用受到高度调节, 对血管形成和功能很重要。在这里,我们将探讨两种不同的功能, 我们最近发现的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 在正常的血管发育过程中,泛素连接酶引起异常的VE-cad内吞作用 和退化。Aim 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的血管发育。目标2研究将 关注在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,并在发育和皮肤病期间靶向VE-钙粘蛋白降解。完成 这些研究将促进我们对钙粘蛋白粘附机制的理解,并揭示 调节血管生成和不适当的血管消退的可能的治疗靶点。

项目成果

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ANDREW P. KOWALCZYK其他文献

ANDREW P. KOWALCZYK的其他文献

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{{ truncateString('ANDREW P. KOWALCZYK', 18)}}的其他基金

Keratinocyte adhesion and signaling in the skin blistering disease pemphigus vulgaris
皮肤起疱病寻常型天疱疮中的角质形成细胞粘附和信号传导
  • 批准号:
    10732360
  • 财政年份:
    2023
  • 资助金额:
    $ 47.9万
  • 项目类别:
Cadherin regulation in dermal endothelial cells
真皮内皮细胞中钙粘蛋白的调节
  • 批准号:
    8526381
  • 财政年份:
    2004
  • 资助金额:
    $ 47.9万
  • 项目类别:
Cadherin Regulation in Dermal Endothelial Cells
真皮内皮细胞中钙粘蛋白的调节
  • 批准号:
    9381479
  • 财政年份:
    2004
  • 资助金额:
    $ 47.9万
  • 项目类别:
Cadherin Regulation in Dermal Endothelial Cells
真皮内皮细胞中钙粘蛋白的调节
  • 批准号:
    7227094
  • 财政年份:
    2004
  • 资助金额:
    $ 47.9万
  • 项目类别:
Cadherin Regulation in Dermal Endothelial Cells
真皮内皮细胞中钙粘蛋白的调节
  • 批准号:
    6929228
  • 财政年份:
    2004
  • 资助金额:
    $ 47.9万
  • 项目类别:
Cadherin Regulation in Dermal Endothelial Cells
真皮内皮细胞中钙粘蛋白的调节
  • 批准号:
    6820500
  • 财政年份:
    2004
  • 资助金额:
    $ 47.9万
  • 项目类别:
Cadherin Regulation in Dermal Endothelial Cells
真皮内皮细胞中钙粘蛋白的调节
  • 批准号:
    9982790
  • 财政年份:
    2004
  • 资助金额:
    $ 47.9万
  • 项目类别:
Cadherin regulation in dermal endothelial cells
真皮内皮细胞中钙粘蛋白的调节
  • 批准号:
    7727763
  • 财政年份:
    2004
  • 资助金额:
    $ 47.9万
  • 项目类别:
Cadherin regulation in dermal endothelial cells
真皮内皮细胞中钙粘蛋白的调节
  • 批准号:
    8185601
  • 财政年份:
    2004
  • 资助金额:
    $ 47.9万
  • 项目类别:
Cadherin regulation in dermal endothelial cells
真皮内皮细胞中钙粘蛋白的调节
  • 批准号:
    7934482
  • 财政年份:
    2004
  • 资助金额:
    $ 47.9万
  • 项目类别:

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由两类细菌肌动蛋白 MreB 驱动的新型运动系统
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