NICHE SPECIFIC PATHOBIOLOGY OF CANDIDA ALBICANS

白色念珠菌的特定病理学

• 批准号: 6374297
• 负责人: William A. Fonzi
• 金额: $ 23.31万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374297
• 关键词: Candida albicans; DNA binding protein; DNA footprinting; biological polymorphism; fungal genetics; gel mobility shift assay; gene expression; genetic regulation; green fluorescent proteins; host organism interaction; immunofluorescence technique; membrane proteins; molecular cloning; molecular pathology; protein protein interaction; protein structure function; regulatory gene; transcription factor; virulence

DESCRIPTION: (Adapted from Applicant's Abstract) Candida albicans is an opportunistic pathogen of AIDS patients. These individuals typically develop oral and esophageal infections due to this fungus. More recently, candidemia has been recognized as a nosocomial complication in AIDS patients with significant associated mortality. Long-term and prophylactic antifungal treatment of AIDS patients has resulted in the emergence of clinically resistant C. albicans strains. This situation is exacerbated by the limited arsenal of efficacious drugs. Much of the biology of C. albicans is unknown due, in part, to the past difficulties in the genetic manipulation of this fungus. However, a substantial amount of data implicate the dimorphic ability of C. albicans in the development of disease. In the case of C. albicans, dimorphism refers to the ability of this organism to adopt either a yeast (single-celled) or hyphal (multicellular filamentous) morphology. The relatively recent development of methods to overcome many of the technical problems in the genetic dissection of C. albicans now permits a closer mechanistic examination of the role of dimorphism in disease. The aim of the present proposal is the investigation of a particular genetic determinant of dimorphism in C. albicans, the gene HWP1. HWP1 was isolated in a screen for genes expressed only in the filamentous form. HWP1 is required for filamentation and virulence in a mouse model of systemic disease, but is not required for gastrointestinal infection in mice nor for filament formation in the gut. This is the first demonstration that the pathogenic attribute of dimorphism has biological facets unique to mucosal vs. systemic disease. The investigators propose a series of molecular genetic studies to define the mechanism(s) governing the development-specific expression of HWP1 in vitro and in vivo and the function of the encoded protein in hyphal development. These studies are set forth with the long-term objective of understanding the molecular basis of pathogenesis by C. albicans and that this knowledge may contribute to better approaches to disease prevention and treatment.

描述：(改编自申请者摘要)白色念珠菌是一种 艾滋病患者的机会性病原体。这些人通常会发展成 这种真菌引起的口腔和食道感染。最近，念珠菌症 已被认为是艾滋病患者的医院并发症 显著的相关死亡率。长期预防性抗真菌药物 艾滋病患者的治疗导致了临床上的出现 耐药的白色念珠菌菌株。这种情况因有限的 有效药物的军火库。白念珠菌的许多生物学特性尚不清楚。 这在一定程度上是由于过去在基因操作方面的困难 真菌。然而，大量的数据暗示了这种二态能力 白念珠菌在疾病发展中的作用。在白色念珠菌的案例中， 二形性是指这种有机体接受一种酵母菌的能力 (单细胞)或菌丝(多细胞丝状)形态。这个 相对较新的发展方法，以克服许多技术上的 白念珠菌基因解剖中的问题现在允许更近距离的 二形性在疾病中作用的机械论检验。该计划的目的是 目前的建议是对一种特定的基因决定因素进行调查 在白色念珠菌中，HWP1基因具有二型性。HWP1是在筛查中分离出来的 基因只以丝状形式表达。以下项目需要HWP1 在全身性疾病小鼠模型中的丝状化和毒力，但不是 小鼠胃肠道感染所需的，也不是细丝形成所需的 我的直觉。这是首次证明了黄连的致病属性 二相性具有粘膜疾病与全身疾病所特有的生物学特征。这个 研究人员提出了一系列分子遗传学研究来定义 HWP1发育特异性表达的体外调控机制(S) 在体内以及编码蛋白在菌丝发育中的作用。这些 开展研究的长期目标是了解 白念珠菌致病的分子基础，这一知识可能 为更好地预防和治疗疾病作出贡献。