AIDS Related Oral Candidiasis: Drugs, Sterols, and Fungal Cells

艾滋病相关的口腔念珠菌病：药物、甾醇和真菌细胞

• 批准号: 7751894
• 负责人: Theodore C. White
• 金额: $ 39.63万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751894
• 关键词: Acquired Immunodeficiency Syndrome; Active Biological Transport; Affect; Anabolism; Antifungal Agents; Antifungal Therapy; Area; Azole resistance; Azoles; Biochemical; Biological Assay; Candida albicans; Cell Communication; Cell Cycle; Cell membrane; Cell surface; Cells; Clinical; Complex; Cues; Data; Diagnosis; Drug Interactions; Effectiveness; Environment; Environmental Risk Factor; Enzymes; Ergosterol; Fluconazole; Fungal Components; Future; Gene Expression; Genes; Goals; Immune; In Vitro; Indium-111; Lead; Mediating; Messenger RNA; Metabolism; Mycoses; Nitrogen; Oral; Oral candidiasis; Oxygen; Patients; Pharmaceutical Preparations; Point Mutation; Poison; Population; Predisposition; Prevention; Probability; Process; Regulation; Research; Research Personnel; Resistance; Resistance development; Resistance to infection; Source; Sterol Biosynthesis Pathway; Sterols; Testing; Transcriptional Regulation; Yeasts; clinically significant; efflux pump; improved; insight; overexpression; patient population; resistance mechanism; resistant strain; response; transcription factor; uptake

The pathogenic yeast Candida albicans (Ca) is a major cause of fungal infections in immune- compromised populations including AIDS patients. It is usually treated with antifungal drugs, most commonly the azole fluconazole which is used extensively in AIDS patients. In these patients, there is a significant probability that azole resistance will develop. Using oral resistant isolates from AIDS patients, major mechanisms of resistance have been identified including alterations in ERG11 (a gene encoding an enzyme in ergosterol biosynthesis and target of the azoles) and increased expression of efflux pumps. Ergosterol is the major sterol in the fungal plasma membrane; and its biosynthesis is the target for azoles and many other antifungals The interaction of fungal cells with azoles is a complex process. Specific aspects of metabolism and the environment influence drug/cell interactions in vitro and have the potential to be important clinically. The Overall Goal of this research is to understand how a fungal cell responds to azoles. This proposal investigates import, subsequent regulation of sterols by the UPC2 transcription factor, and the influence of environmental factors on the cellular response to drugs. The Specific Aims of this proposal are: 1. To characterize fluconazole import into the fungal cell. Azole import is important to the cell/drug interaction; it may be mediated by passive or active transport; and it has not been studied previously. 2. To analyze the transcriptional regulation of UPC2. Once within the cell, azoles inhibit Erg 11 p, altering sterol levels, and activating the UPC2 transcription factor, which regulates sterol biosynthesis and uptake. Regulation of the UPC2 gene will be analyzed to understand how changes in sterol metabolism, including uptake and biosynthesis are correlated with expression of UPC2. 3. To characterize the effect of specific environmental factors on drug susceptibility and the cell surface. Environmental factors, including pH, oxygen levels, nitrogen sources, and exogenous sterols, will be analyzed for their effect on the drug susceptibility and the cell surface, using microbiological, biochemical and gene expression approaches. 4. To characterize clinical isolates for alterations in sterol metabolism. The known mechanisms of resistance do not apply to many resistant strains. This aim will assay import, UPC2 regulation, and response to environmental factors to identify possible new resistance mechanisms in these isolates. Understanding the interactions between azoles and fungal cells is a clinically significant issue, with the potential for improving diagnosis, treatment and prevention of fungal infections and resistance.

致病性酵母菌白色念珠菌（Ca）是引起免疫系统真菌感染的主要原因