CANDIDA ADHERENCE AND PENETRATION OF VASCULAR ENDOTHELIUM

念珠菌对血管内皮的粘附和穿透

• 批准号: 7376103
• 负责人: John E Edwards
• 金额: $ 1.83万
• 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: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376103
• 关键词: CANDIDA; ADHERENCE; PENETRATION; VASCULAR; ENDOTHELIUM

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. While potent antifungal agents exist that are microbicidal for Candida, the attributable mortality of candidemia is approximately 38%, even with treatment. It is likely that additional antifungals may be developed that are less toxic than amphotericin B. However, it is unlikely that agents will be developed that are more potent. Therefore our long range goals are focused on strategies to enhance the immune and inflammatory responses to Candida for use as adjunctive therapy to the currently available and future antifungal agents. In recent years studies from many laboratories, as well as our own, have shown that endothelial cells play a major role in modifying the inflammatory response. Investigating the interactions of Candida with vascular endothelium has the potential to lead to novel strategies to use endothelial cells to enhance host defense mechanisms. We propose to extend our previous investigations on the molecular mechanisms of the adherence of Candida to endothelial cells, and on the defense mechanisms by which endothelial cells resist damage and invasion by this organism in vitro and in vivo. These studies are aimed at exploring the hypothesis that 1) blocking the adherence of Candida to endothelial cells will prevent their egress from the intravascular compartment, and 2) endothelial ces have mechanisms to resist damage by Candida. These mechanisms are targets to explore for therapeutic up-regulation. These two hypothesis will be evaluated by pursuit of the following specific aims: To determine the role of the ALS1 gene product in mediating the adherence of Candida albicans to human vascular endothelial cells. To determine the mechanisms by which endothelial cells escape damage when C. Albicans is killed by neutrophils on endothelium. To determine whether the immunomodulators and candidal virulence factors identified in our in vitro experiments are expressed at sites of candidal infection in humans with hematogenously disseminated candidiasis.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。虽然存在对念珠菌具有杀微生物作用的强效抗真菌剂，但即使经过治疗，念珠菌血症的归因死亡率仍约为38%。很可能会开发出毒性低于阿替霉素B的其他抗真菌药。然而，不太可能开发出更有效的药剂。因此，我们的长期目标集中在增强对念珠菌的免疫和炎症反应的策略上，以用作对目前可用的和未来的抗真菌剂的连续治疗。近年来，许多实验室以及我们自己的研究表明，内皮细胞在调节炎症反应中起着重要作用。研究念珠菌与血管内皮的相互作用有可能产生利用内皮细胞增强宿主防御机制的新策略。我们建议扩展我们之前对念珠菌粘附内皮细胞的分子机制以及内皮细胞在体外和体内抵抗该生物体损伤和入侵的防御机制的研究。这些研究旨在探索以下假设：1）阻断念珠菌与内皮细胞的粘附将阻止其从血管内室中流出，以及2）内皮细胞具有抵抗念珠菌损伤的机制。这些机制是探索治疗上调的靶点。这两个假设将通过追求以下具体目标进行评估：确定ALS 1基因产物在介导白色念珠菌粘附到人血管内皮细胞中的作用。为了确定C.白细胞被内皮细胞上的中性粒细胞杀死。确定在我们的体外实验中鉴定的免疫调节剂和念珠菌毒力因子是否在人类血源性播散性念珠菌病的念珠菌感染部位表达。