Regulation of Morphogenesis in C. albicans

这项建议的目的是确定白色念珠菌形态发生的分子机制。白色念珠菌是人类最常见的真菌病原体，在免疫功能受损的人中会引起特别严重的危及生命的感染。随着更好的医疗技术使器官移植、癌症和艾滋病毒患者的长期护理变得更加普遍，白色念珠菌作为健康风险的重要性正在增加。为了制定新的治疗策略来对抗白念珠菌病，需要更好地了解其发病机制，因为目前使用的治疗白色念珠菌的药物并不是很有效，特别是在它侵入组织之后。与白念珠菌致病密切相关的一个毒力因子是这种酵母在圆形萌发细胞和丝状菌丝之间经历形态转换的能力。因此，这笔赠款的具体目的是为了识别调节白念珠菌形态发生的蛋白质。特别是，细胞骨架蛋白的间隔蛋白家族将被研究，因为间隔蛋白在酵母、酿酒酵母和其他生物的形态转变中扮演着重要的角色。遗传策略将被用来确定Septin家族中哪些成员在菌丝形态发生中发挥作用。然后将使用生化方法来研究调节白色念珠菌Septin蛋白的机制，并将使用定向突变来确定它们在控制菌丝形态发生中的作用。Septins通过招募关键的调节蛋白发挥作用。因此，通过鉴定Septin结合蛋白并分析它们的功能，将进一步明确Septin在白念珠菌中的功能。这些实验程序旨在充分利用最近改进的白念珠菌基因分析策略和白念珠菌基因组测序项目提供的数据。总之，这些研究有望确定促进白念珠菌发病的形态转变的关键调控因素。

The goal of this proposal is to determine the molecular mechanisms of morphogenesis for Candida albicans. C. albicans is the most common fungal pathogen in humans and causes particularly severe life-threatening infections in immunocompromised individuals. The significance of C. albicans as a health risk is increasing as better medical techniques make long-term care of organ transplant, cancer, and HIV patients more common. A better understanding of the mechanisms of pathogenesis is needed to formulate new therapeutic strategies to combat Candidiasis because the drugs currently used against C. albicans are not very effective, especially after it has invaded into tissues. One virulence factor that has been strongly implicated in the pathogenesis of C. albicans is the ability of this yeast to undergo morphological transitions between round budding cells and filamentous hyphae. Therefore, the specific aims of this grant are designed to identify the proteins that regulate morphogenesis of C. albicans. In particular, the septin family of cytoskeletal proteins will be examined because the septins play important roles in morphological transitions in the yeast S. cerevisiae and other organisms. Genetic strategies will be used to determine which members of the septin family function in hyphal morphogenesis. Biochemical approaches will then be used to study the mechanisms that regulate C. albicans septin proteins, and targeted mutagenesis will be used to determine their role in controlling hyphal morphogenesis. Septins act by recruiting key regulatory proteins. Therefore, Septin function in C. albicans will be defined further by identifying septin-binding proteins and analyzing their function. The experimental procedures are designed to take full advantage of recently improved strategies for the genetic analysis of C. albicans and the data being made available from the C. albicans genome sequencing project. Altogether, these studies are expected to identify key regulators of morphological transitions that promote the pathogenesis of C. albicans.