Aspergillus Angioinvasion and Dissemination

曲霉菌血管侵袭和传播

• 批准号: 6906824
• 负责人: Scott G Filler
• 金额: $ 13.66万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906824
• 关键词: Aspergillus; aspergillosis; blood tests; cell adhesion; cellular pathology; clinical research; disease /disorder model; extracellular matrix proteins; host organism interaction; human subject; immunocytochemistry; laboratory mouse; parasite infection mechanism; respiratory infections; tissue /cell culture; transmission electron microscopy; umbilical cord; vascular endothelium; virulence

DESCRIPTION (provided by the applicant): Invasive infections due to Aspergillus fumigatus are increasing, and despite new therapies are associated with greater than 50% mortality. Invasion of blood vessels is a hallmark pathologic feature of invasive aspergillosis and plays a critical role in the development of local and disseminated disease. This process of angioinvasion and subsequent dissemination is unique to A. fumigatus and a handful of other pathogenic molds, and its mechanism is not well understood. Histopathologic studies suggest that there are several key steps by which the organism gains entry to and subsequently exits from the vascular system. First, hyphae from an infectious focus must invade the abluminal surface of the blood vessel, and penetrate endothelial cells to gain access to the blood vessel lumen. Next, hyphal fragments are borne by the bloodstream to distal sites where they adhere to and penetrate the luminal surface of the endothelial cells lining the blood vessel and thereby invade the deep organs. Our overall hypothesis is that the interactions of A. fumigatus with the vascular endothelium are critical to the pathogenesis of invasive aspergillosis. We propose to study the mechanisms underlying angioinvasion and hematogenous dissemination by first developing an in vitro culture system that will enable us to study the interactions of A. fumigatus with both the abluminal and luminal surfaces of the endothelial cell. Using this system, we will investigate the mechanisms of endothelial cell invasion, stimulation, and injury when hyphae infect the abluminal vs. luminal surfaces of the endothelial cell. We will also characterize the parameters that govern the luminal adherence of A. fumigatus hyphae to endothelium and subendothelial matrix proteins. Finally, we will validate our in vitro results using two new murine models of invasive pulmonary and hematogenously disseminated aspergillosis. These studies are designed to lay the essential foundation for a comprehensive research program aimed at elucidating the molecular mechanisms by which A. fumigatus invades blood vessels and hematogenously disseminates.

描述（由申请人提供）：烟曲霉引起的侵袭性感染正在增加，尽管有新的疗法，但其死亡率仍超过 50%。血管侵袭是侵袭性曲霉病的标志性病理特征，在局部和播散性疾病的发展中起着关键作用。这种血管侵袭和随后传播的过程是烟曲霉和少数其他致病霉菌所独有的，其机制尚不清楚。组织病理学研究表明，生物体进入并随后离开血管系统有几个关键步骤。首先，来自感染灶的菌丝必须侵入血管的近腔表面，并穿透内皮细胞以进入血管腔。接下来，菌丝碎片被血流带到远端部位，在那里它们粘附并穿透血管内皮细胞的管腔表面，从而侵入深部器官。我们的总体假设是烟曲霉与血管内皮的相互作用对于侵袭性曲霉病的发病机制至关重要。我们建议通过首先开发体外培养系统来研究血管侵袭和血行传播的机制，该系统将使我们能够研究烟曲霉与内皮细胞的近腔和腔表面的相互作用。使用该系统，我们将研究当菌丝感染内皮细胞的近腔表面和腔表面时内皮细胞侵袭、刺激和损伤的机制。我们还将表征控制烟曲霉菌丝与内皮和内皮下基质蛋白的管腔粘附的参数。最后，我们将使用两种新的侵袭性肺曲霉病和血行播散性曲霉病小鼠模型来验证我们的体外结果。这些研究旨在为旨在阐明烟曲霉侵入血管和血行传播的分子机制的综合研究计划奠定重要基础。