CANDIDA ADHERENCE AND PENETRATION OF VASCULAR ENDOTHELIUM

念珠菌对血管内皮的粘附和穿透

• 批准号: 7952280
• 负责人: John E Edwards
• 金额: $ 0.66万
• 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: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7952280
• 关键词: Adherence; Amphotericin B; Antifungal Agents; Candida; Candida albicans; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Defense Mechanisms; Disseminated candidiasis; Endothelial Cells; Endothelium; Funding; Future; Goals; Grant; Host Defense Mechanism; Human; Immune; Immunomodulators; In Vitro; Infection; Inflammatory Response; Institution; Investigation; Laboratories; Lead; Mediating; Molecular; Organism; Penetration; Play; Proteins; Research; Research Personnel; Resources; Role; Site; Source; Therapeutic; United States National Institutes of Health; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelium; Virulence Factors; attributable mortality; candidemia; in vivo; killings; microbicide; neutrophil; novel strategies; prevent; research study

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 虽然存在有效的抗真菌剂，这些抗真菌剂是念珠菌的杀生剂，但即使经过治疗，候选念珠菌的归因死亡率也约为38％。可能会开发出比两性霉素的毒性更低的其他抗真菌剂。但是，不太可能开发出更有效的代理。因此，我们的远距离目标集中在策略上，以增强对念珠菌的免疫和炎症反应，以用作当前可用和未来抗真菌药物的辅助疗法。近年来，来自许多实验室以及我们自己的研究表明，内皮细胞在修饰炎症​​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导致使用内皮细胞增强宿主防御机制的新型策略。我们建议扩展我们先前对念珠菌对内皮细胞粘附的分子机制的研究，以及内皮细胞在体外和体内抵抗这种生物体损害和侵袭的防御机制。这些研究的目的是探讨以下假设：1）阻止念珠菌对内皮细胞的粘附将阻止其从血管内室中流出，而2）内皮CE具有抵抗念珠菌损害的机制。这些机制是探索治疗上调的目标。这两个假设将通过追求以下特定目的来评估：确定ALS1基因产物在介导白色念珠菌对人血管内皮细胞的依从性方面的作用。确定当白色念珠菌在内皮上被嗜中性粒细胞杀死时，内皮细胞逃脱损害的机制。为了确定在我们的体外实验中鉴定的免疫调节剂和候选毒力因子是否在患有血源性传播念珠菌病的人类的候选感染部位表达。