Ras Signaling in C. neoformans virulence and development

描述（由申请人提供）：项目概述。引起人类疾病的微生物必须能够对宿主环境中遇到的压力作出反应。这些细胞反应包括形态发生的改变，或决定细胞大小、形状和体积的细胞骨架的修饰。本提案的长期目标是确定允许微生物病原体调节这些过程并适应受感染宿主的敌对环境的分子事件。人类真菌病原体新隐球菌是了解微生物发病机制基本问题的重要模型系统。在宿主-寄生虫相互作用过程中遇到的应激反应中，新生C.在其细胞骨架中显示出可复制的改变。这些形态发生反应使细胞能够适应高温和其他宿主特定的条件。Ras1蛋白控制胞内信号事件，这些信号事件指导了许多适应性细胞反应。本提案中的实验将定义C. neoformans使用Ras1和一系列级联蛋白相互作用在宿主内生存和生长的方式。首先，将研究Ras1形态发生途径的独特成分，以确定这些蛋白如何在37℃下特异性地指导形态发生和生长。其次，将创建一个微阵列数据纲要，以更全面地定义那些在Ras1信号通路的各个分支中起作用的蛋白质。最后，我们将研究Ras蛋白在细胞内的定位，以确定其在微生物病原体中决定Ras信号特异性的作用。相关性:。确定微生物与其宿主相互作用的方式将有助于更好地理解和治疗传染病。本提案中的研究将描述Ras蛋白允许微生物对感染宿主内遇到的压力作出反应的方式。Ras及其相关蛋白的操作直接影响微生物的生存，并为开发新的抗感染疗法提供了独特的选择。

DESCRIPTION (provided by applicant): Project summary. Microorganisms that cause human disease must be able to respond to stresses encountered in the host environment. These cellular responses include morphogenic changes, or modifications of the cytoskeleton that determine cell size, shape, and volume. The long-term goals of this proposal are to define the molecular events that allow microbial pathogens to regulate these processes and adapt to the hostile environment of the infected host. The human fungal pathogen Cryptococcus neoformans is an important model system for understanding basic issues in microbial pathogenesis. In response to stresses encountered during a host-parasite interaction, C. neoformans displays reproducible alterations in its cytoskeleton. These morphogenic responses allow the cell to adapt to elevated temperatures and other host-specific conditions. The Ras1 protein controls the intracellular signaling events that direct many of these adaptive cellular responses. The experiments in this proposal will define the ways in which C. neoformans uses Ras1 and a cascading series of protein interactions to survive and grow within the host. First, unique components of the Ras1 morphogenesis pathways will be studied to determine how these proteins specifically direct morphogenesis and growth at 37C. Second, a compendium of microarray data will be created to more fully define those proteins that function in the various arms of the Ras1 signaling pathways. Finally, Ras protein localization within the cell will be studied to define its role in determining Ras signaling specificity in a microbial pathogen. Relevance:. Defining the ways in which microorganisms interact with their host will result in better understanding and treatment of infectious diseases. The studies in this proposal will characterize the ways in which Ras proteins allow microorganisms to respond to the stresses encountered within the infected host. Manipulation of Ras and its related proteins directly affects microbial survival and offers a unique option for the development of new anti-infective therapies. NARRATIVE : Defining the ways in which microorganisms interact with their host will result in better understanding and treatment of infectious diseases. The studies in this proposal will characterize the ways in which Ras proteins allow microorganisms to respond to the stresses encountered within the infected host. Manipulation of Ras and its related proteins directly affects microbial survival and offers a unique option for the development of new anti-infective therapies.