Azoles and Candida in AIDS-Transcriptional Regulation

描述(申请人提供)：白色念珠菌，一种致病酵母菌，是包括艾滋病患者在内的免疫受损患者群体中真菌感染的原因。这些感染是用包括唑类氟康唑在内的抗真菌药物治疗的。广泛使用唑类药物导致了耐药性，这是一个日益严重的问题。随着抗性分子机制的确定，了解在敏感和耐药菌株中调节这些机制的途径变得重要。目前，关于ERG11基因在白色念珠菌中的转录调控知之甚少，其产物是唑类药物的靶标，也是合成麦角甾醇的生物合成步骤，麦角甾醇是真菌中相当于胆固醇的物质。这项研究的总体目标是通过研究与耐药性相关的基因的表达和调控来了解氮唑类药物和白色念珠菌之间的相互作用。这项建议的重点是ERG11的转录调控。具体目的是：1)鉴定ERG11启动子中对转录调控重要的区域。2)鉴定和鉴定调控ERG11启动子的转录因子。3)研究新近发现的白念珠菌ECM22转录因子对ERG11和唑类药物敏感性的影响；基因突变可导致唑类药物的超敏反应。4)鉴定通过基因组方法鉴定的其他白色念珠菌基因，这些基因可以调节唑类药物的敏感性。在可预见的未来，唑类药物与真菌细胞之间的相互作用，以及由此产生的唑类耐药性，将继续是一个具有临床意义的问题。了解ERG11和麦角甾醇生物合成的转录调控，以及了解真菌细胞对唑类药物的反应可能有助于改进真菌感染和耐药性的诊断、治疗和预防。

DESCRIPTION (provided by applicant): Candida albicans, a pathogenic yeast, is the cause of fungal infections in immune-compromised patient populations including AIDS patients. These infections are treated with antifungal drugs including the azole fluconazole. Extensive azole use has resulted in resistance which is a growing and significant problem. As molecular mechanisms of resistance are identified, it becomes important to understand the pathways which regulate these mechanisms in both susceptible and resistant strains. Currently, little is known about the transcriptional regulation of the ERG11 gene in C. albicans, the product of which is the target of the azole drugs and a biosynthetic step in the synthesis of ergosterol, the fungal equivalent of cholesterol. The Overall Goal of this research is to understand the interactions between azoles and C. albicans by studying the expression and regulation of genes associated with resistance. This proposal focuses on the transcriptional regulation of ERG11. The Specific Aims are: 1) To characterize regions of the ERG11 promoter that are important for transcriptional regulation. 2) To identify and characterize the transcription factors that regulate the ERG11 promoter. 3) To characterize the newly described ECM22 transcription factor in C. albicans for its effect on ERG11 and azole susceptibility; disruption of gene results in azole hyper-susceptibility. 4) To characterize additional C. albicans genes, identified by genomic approaches, that regulate azole susceptibility. The interactions between azoles and fungal cells, and the resulting azole drug resistance, will continue to be a clinically significant issue for the foreseeable future. Understanding the transcriptional regulation of ERG11 and of ergosterol biosynthesis, and understanding how fungal cells respond to azole drugs may lead to improvements in diagnosis, treatment and prevention of fungal infections and of resistance.