The role of the CCAAT-binding factor in Candida albicans

描述（由申请人提供）：白色念珠菌是人类最常见的真菌病原体，可引起多种皮肤和全身性感染。有许多诱发因素导致念珠菌感染;然而，免疫功能低下患者（主要是由于免疫抑制治疗和艾滋病）数量的增加导致念珠菌病的发病率急剧增加。这一事实，再加上有限的治疗药物库，决定了目前的研究工作集中在阐明途径，有助于念珠菌毒力和确定新的药物开发的目标。这项研究计划的长期目标是研究真菌CCAAT结合因子的独特结构特征是否可以作为抗真菌化合物的靶点。CCAAT结合因子是一种异源寡聚体转录激活因子，在所有真核生物中进化上高度保守;然而，在真菌中，该转录因子包含在其他真核生物中未发现的新亚基（称为Hap 4p）。正是这种真菌特异性亚基与异聚体复合物的其他组分的独特相互作用代表了药物开发的潜在靶点。Hap 4p与复合物的DNA结合组分相互作用的失败导致靶基因表达的丧失。因此，开发抑制这种真菌特异性蛋白质-蛋白质相互作用的肽或小分子可以提供对抗真菌感染的可行方法。本提案中描述的研究目标是确定C中CCAAT结合因子的调节功能。白念珠菌，并检查它是否是重要的参与毒力和发病机制的基因调控，作为探索其作为治疗药物靶点的潜力的第一步。本研究的主要目的是：1）在编码CCAAT结合因子不同亚基的基因中产生突变体并评估其表型; 2）确定CCAAT结合因子是否对C.白念珠菌的毒力;和3）解剖CCAAT结合因子的调节功能。

DESCRIPTION (provided by applicant): Candida albicans is the most frequently encountered fungal pathogen in humans, and is responsible for a variety of rnucocutaneous and systemic infections. There are a number of predisposing factors that contribute to Candida infections; however, the increasing number of immunocompromised patients (due primarily to imrnunosuppressive therapies and AIDS) has led to a sharp increase in the incidence of candidiasis. This fact, coupled with the limited arsenal of therapeutic agents, dictates that current research efforts focus on elucidating pathways that contribute to Candida virulence and on identifying novel targets for drug development. The long-term goal of this research program is to investigate whether a unique structural feature of fungal CCAAT-binding factors could serve as a target for antifungal compounds. The CCAAT-binding factor is a heterooligomeric transcriptional activator that is highly conserved evolutionarily in all eukaryotes; however, in fungi this transcription factor contains a novel subunit (termed Hap4p) that is not found in other eukaryotes. It is the unique interaction of this fungal-specific subunit with other components of the heteromeric complex that represents a potential target for drug development. The failure of Hap4p to interact with the DNA-binding components of the complex results in the loss of target gene expression. Thus, development of peptides or small molecules that inhibit this fungal-specific protein-protein interaction could offer a viable approach to combating fungal infections. The goal of the studies described in this proposal is to determine the regulatory function of the CCAAT-binding factor in C. albicans, and to examine whether it is important in the regulation of genes involved in virulence and pathogenesis, as the initial step toward exploring its potential as a therapeutic drug target. The proposed studies will address the following specific aims: 1) to generate mutants in the genes encoding the various subunits of the CCAAT-binding factor and evaluate their phenotypes; 2) to determine whether the CCAAT-binding factor is important for C. albicans virulence; and 3) to dissect the regulatory function of the CCAAT-binding factor.