The role of the CCAAT-binding factor in Candida albicans

超出所提供的空间。念珠菌（Candic/a /bicans）是人类最常见的真菌病原体，可引起多种皮肤和全身感染。有许多诱发因素可导致癌症/ida感染；然而，越来越多的免疫功能低下的患者（主要是由于免疫抑制疗法和艾滋病）导致念珠菌病的发病率急剧增加。这一事实，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有助于念珠菌毒力的途径和确定药物开发的新靶点上。该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标。ccaat结合因子是一种在所有真核生物中高度保守的异聚转录激活因子；然而，在真菌中，这种转录因子含有一个新的亚基（称为Hap4p），在其他真核生物中没有发现。这是这种真菌特异性亚基与异质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目标。Hap4p无法与复合体的dna结合成分相互作用，导致靶基因表达缺失。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能为对抗真菌感染提供一种可行的方法。本研究的目的是确定ccaat结合因子在白色念珠菌中的调节功能，并检查其是否在调节涉及毒力和发病机制的基因中起重要作用，作为探索其作为治疗药物靶点潜力的第一步。拟建的研究将解决以下具体目标：1)在编码ccaat结合因子的各种亚基的基因中产生突变并评估其表型；2)确定ccaat结合因子是否对白色念珠菌毒力有重要影响；3)剖析ccaat结合因子的调控功能。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================