Azoles and Candida in AIDS-Transcriptional Regulation

描述（由申请人提供）：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群体真菌感染的原因。这些感染用抗真菌药物治疗，包括唑氟康唑。广泛使用唑已导致耐药性，这是一个日益严重的问题。随着耐药分子机制的确定，了解在易感和耐药菌株中调控这些机制的途径变得非常重要。目前，对白色念珠菌中ERG11基因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（相当于真菌中的胆固醇）的生物合成步骤。本研究的总体目标是通过研究与抗性相关基因的表达和调控来了解唑类药物与白色念珠菌之间的相互作用。本文主要研究ERG11的转录调控。具体目的是：1)表征ERG11启动子中对转录调控重要的区域。2)鉴定和表征调控ERG11启动子的转录因子。3)研究新发现的ECM22转录因子在白色念珠菌中对ERG11和唑类药物敏感性的影响；基因的破坏导致了唑的超敏感性。4)通过基因组学方法鉴定出调节唑敏感性的其他白色念珠菌基因。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药物耐药性仍将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，以及真菌细胞对唑类药物的反应，可能有助于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.