Azoles and Candida in AIDS-Transcriptional Regulation

描述（由申请方提供）：白色念珠菌是一种致病性酵母菌，是包括艾滋病患者在内的免疫功能低下患者人群真菌感染的原因。这些感染可以用抗真菌药物治疗，包括唑类氟康唑。广泛使用唑类药物已导致耐药性，这是一个日益严重的问题。随着耐药的分子机制的确定，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，对C.白念珠菌，其产物是唑类药物的靶点，也是麦角甾醇（胆固醇的真菌等价物）合成中的生物合成步骤。本研究的总体目标是了解唑类化合物与C.通过研究与耐药相关基因的表达和调控，该提案的重点是ERG 11的转录调控。具体目的是：1）表征ERG 11启动子中对转录调控重要的区域。2)鉴定和表征调控ERG 11启动子的转录因子。3)为了鉴定新发现的C.白念珠菌对ERG 11和唑类药物敏感性的影响;基因破坏导致唑类药物超敏感性。4)为了表征额外的C.通过基因组方法鉴定的调节唑类药物敏感性的白念珠菌基因。唑类和真菌细胞之间的相互作用，以及由此产生的唑类耐药性，在可预见的未来将继续成为临床上重要的问题。了解ERG 11和麦角固醇生物合成的转录调控，以及了解真菌细胞如何对唑类药物作出反应，可能会改善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.