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: 7173458
• 负责人: Theodore C. White
• 金额: $ 40.48万
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173458
• 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; Condition; 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; Protein Overexpression; Regulation; Research; Research Personnel; Resistance; Resistance development; Resistance to infection; Source; Standards of Weights and Measures; Sterol Biosynthesis Pathway; Sterols; Testing; Transcriptional Regulation; Yeasts; clinically significant; efflux pump; improved; insight; resistance mechanism; response; transcription factor; uptake

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：病原性酵母白色念珠菌（CA）是包括艾滋病患者在内的免疫受损人群中真菌感染的主要原因。它通常是用抗真菌药物治疗的，最常见的是甲唑氟康唑，该氟康唑广泛用于艾滋病患者。在这些患者中，偶氮耐药性会产生很大的可能性。使用来自艾滋病患者的口服抗性分离株，已经确定了主要的耐药机制，包括改变ERG11的改变（一种编码麦角固醇生物合成酶的基因和硫唑的靶标）和外排泵的表达增加。麦角固醇是真菌质膜中的主要固醇。它的生物合成是Azole和许多其他抗真菌剂的靶标。真菌细胞与偶氮的相互作用是一个复杂的过程。代谢的特定方面和环境会在体外影响药物/细胞相互作用，并且有可能在临床上变得重要。这项研究的总体目标是了解真菌细胞如何对偶氮对象做出反应。该提案调查了进口，随后通过UPC2转录因子对固醇的调节以及环境因素对细胞对药物反应的影响。该提案的具体目的是：1。表征氟康唑进口到真菌细胞中。 Azole进口对细胞/药物相互作用很重要。它可以通过被动或主动运输介导；而且它以前尚未研究。 2。分析UPC2的转录调节。一旦在细胞内，硫唑会抑制ERG 11 P，改变固醇水平并激活UPC2转录因子，从而调节固醇生物合成和摄取。将分析UPC2基因的调节，以了解固醇代谢的变化（包括摄取和生物合成）如何与UPC2的表达相关。 3。表征特定环境因素对药物敏感性和细胞表面的影响。将使用微生物，生化和基因表达方法分析环境因素，包括pH，氧气水平，氮源和外源固醇，以分析其对药物易感性和细胞表面的影响。 4。表征固醇代谢改变的临床分离株。抗性的已知机制不适用于许多抗性菌株。该目标将分析导入，UPC2调节以及对环境因素的反应，以确定这些分离株中可能的新抗性机制。了解唑唑与真菌细胞之间的相互作用是一个临床上的重要问题，具有改善真菌感染和耐药性的诊断，治疗和预防的潜力。