ENDOTHELIAL PERMEABILITY IN AIRWAY ANGIOGENESIS

这个项目的总体目标是探索新的方法， 在呼吸道血管生成部位的内皮细胞。 为了实现这一目标，我们将描述血管生成的表型， 内皮细胞，使用小鼠血管生成模型和方法， 已经开发用于研究体内内皮细胞生物学。 的 该项目将利用我们最近的发现， 内皮细胞在体内内化阳离子脂质体更多 比他们的正常同行更贪婪。 这些细胞也有一个异常的 与某些植物凝集素的结合模式，并且异常敏感 导致血浆渗漏的炎症介质。这些异常 可能发生在新血管生长的部位，表明迄今为止 血管生成内皮细胞的未识别异质性。 项目 将检验三个假设：第一，血管生成的内皮细胞 血管是异质的。 血管生长部位的细胞 由于它们对阳离子脂质体的强烈吸收而与众不同， 渗漏和腔膜寡糖的表达。第二、 血管生成内皮细胞对阳离子脂质体的强烈摄取 通过受体介导的内吞作用发生。第三， 血管生成内皮细胞是由于异常的易感性， 形成细胞间隙 我们的具体目标是：1）确定地点 在血管生成血管中的新血管生长，并确定 这些部位的内皮细胞具有独特的表型 阳离子脂质体、血浆渗漏和异常凝集素的特征 结合; 2）表征阳离子的亲和结合和摄取 脂质体的血管生成内皮细胞，重点是受体- 介导的内吞作用; 3）确定 血管生成血管 该项目将利用两种模式， 在小鼠血管生成方面，我们有相当丰富的经验。 第一种，由于呼吸道粘膜中的血管生成， 由于肺支原体感染引起的慢性炎症。 在另一 模型，血管生成发生在肿瘤中， SV-40病毒癌基因的表达。 该模型提供了一种方法， 研究在一个井中血管生成内皮细胞的表型变化， 以从正常组织到肿瘤的发展为特征。 阐明 血管生成内皮细胞的独特特征， 他们的血浆蛋白泄漏机制将提供新的 靶向和调节血管生成血管的策略 治疗肺肿瘤和慢性气道炎性疾病， 支气管炎和哮喘。

The overall goal of this project is to explore novel ways of targeting endothelial cells at sites of angiogenesis in the respiratory tract. Toward this goal, we will characterize the phenotype of angiogenic endothelial cells, using models of angiogenesis in mice and methods we have developed for studying endothelial cell biology in vivo. The project will take advantage of our recent discovery that angiogenic endothelial cells in vivo internalize cationic liposomes much more avidly than their normal counterparts. The cells also have an abnormal binding pattern to certain plant lectins and are abnormally sensitive to inflammatory mediators that cause plasma leakage. These abnormalities may occur focally at sites of new vessel growth, indicating a hitherto unrecognized heterogeneity of angiogenic endothelial cells. The project will test three hypotheses: First, endothelial cells of angiogenic blood vessels are heterogeneous. Cells at sites of vessel growth are distinctive because of their avid uptake of cationic liposomes, leakiness, and expression of luminal membrane oligosaccharides. Second, the avid uptake of cationic liposomes by angiogenic endothelial cells occurs by receptor-mediated endocytosis. Third, the leakiness of angiogenic endothelial cells is due to an abnormal susceptibility to form intercellular gaps. Our specific aims are to: 1) identify sites of new vessel growth in angiogenic blood vessels and determine whether the endothelial cells at these sites have the distinctive phenotypic features of cationic liposomes, plasma leakage, and abnormal lectin binding; 2) characterize the avid binding and uptake of cationic liposomes to angiogenic endothelial cells, with a focus on receptor- mediated endocytosis; and 3) determine the mechanism of leakiness of angiogenic vessels. The project will take advantage of two models of angiogenesis in mice with which we have had considerable experience. In the first, angiogenesis develops in the airway mucosa as a result of chronic inflammation due to Mycoplasma pulmonis infection. In the other model, angiogenesis occurs in tumors that result from transgenetic expression of the SV-40 viral oncogene. This model provides a way of studying phenotypic changes in angiogenic endothelial cells in a well- characterized progression from normal tissue to tumors. The elucidation of distinctive features of angiogenic endothelial cells and the mechanism of their leakiness to plasma proteins will provide new strategies for targeting and modulating angiogenic blood vessels in the treatment of lung tumors and chronic airway inflammatory diseases such as bronchitis and asthma.