Regulation of Morphogenesis in C. albicans

本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，在免疫功能低下的个体中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更加普遍，白色念珠菌作为一种健康风险的重要性正在增加。由于目前用于治疗白色念珠菌的药物不是很有效，特别是在它侵入组织后，需要更好地了解其发病机制，以制定新的治疗策略来对抗念珠菌病。一个与白色念珠菌的发病机制密切相关的毒力因素是这种酵母在圆形芽殖细胞和丝状菌丝之间进行形态转变的能力。因此，这项拨款的具体目的是确定调节白色念珠菌形态发生的蛋白质。特别是，细胞骨架蛋白的septin家族将被研究，因为septin在酵母和其他生物的形态转变中起着重要的作用。遗传策略将用于确定septin家族的哪些成员在菌丝形态发生中起作用。生化方法将用于研究调节白色念珠菌septin蛋白的机制，靶向诱变将用于确定其在控制菌丝形态发生中的作用。septin通过招募关键的调节蛋白起作用。因此，通过鉴定Septin结合蛋白并分析其功能，将进一步确定Septin在白色念珠菌中的功能。实验程序旨在充分利用最近改进的白色念珠菌遗传分析策略和白色念珠菌基因组测序计划提供的数据。总之，这些研究有望确定促进白色念珠菌发病机制的形态学转变的关键调节因子。

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.