The role of the CCAAT-binding factor in Candida albicans

Candic/a/bicans是人类最常见的真菌病原体， 引起多种皮肤和全身感染。有许多 导致癌症/IDA感染的诱发因素;然而， 免疫抑制患者（主要是由于免疫抑制治疗和艾滋病） 念珠菌病发病率的急剧上升。这一事实，加上有限的军火库， 治疗剂，决定了目前的研究工作集中在阐明途径， 有助于念珠菌的毒力和确定新的药物开发的目标。长 本研究计划是为了研究真菌的一个独特结构特征， CCAAT结合因子可以作为抗真菌化合物的靶点。CCAAT绑定 因子是一种异源寡聚体转录激活因子，在所有基因组中进化上高度保守， 然而，在真菌中，这种转录因子含有一个新的亚基（称为Hap 4p）， 在其他真核生物中是没有的。正是这种真菌特异性亚基与其他亚基的独特相互作用， 这些化合物是异聚复合物的组成部分，代表了药物开发的潜在靶标。 Hap 4p不能与复合物的DNA结合组分相互作用， 靶基因的表达。因此，开发抑制这种作用的肽或小分子， 真菌特异性蛋白质-蛋白质相互作用可以提供一种对抗真菌的可行方法 感染.本提案中描述的研究目标是确定 CCAAT结合因子在C.白念珠菌，并检查它是否是重要的，在监管 参与毒力和发病机制的基因，作为探索其潜力的第一步， 治疗药物靶点。建议的研究将针对以下具体目标：1） 在编码CCAAT结合因子的各种亚基的基因中产生突变体， 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。

Candic/a a/bicans 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 Canc/ida infections; however, the increasing number of immunocomprornised patients (due primarily to imrnunosuppressive therapies and AIDS) has lead 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 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.