Pheromones and Titan Cell Production in Cryptococcus neoformans

描述（由申请人提供）：信息素和信息素受体长期以来已知会影响机会致病菌新型隐球菌的毒力，但仍然完全不清楚信息素信号传导的生物学分支如何影响发病机制。尼尔森实验室已经表明，一种新的特征细胞类型的产生-被称为“泰坦细胞”-被信息素传感改变。泰坦细胞的过度产生与CNS渗透减少相关。本申请的目的是确定泰坦细胞在发病机制中的作用，以及信息素信号如何改变泰坦细胞的生产。我们的应用程序的中心假设是，信息素信号级联，与其他信号成分，调节泰坦细胞的形成，影响随后的传播到中枢神经系统。这项研究的基本原理是，一旦知道了泰坦细胞在发病机制中的作用以及它们是如何被调节的，泰坦细胞的产生就可以在预防和治疗隐球菌病的新的创新方法中成为目标。我们计划通过追求以下具体目标来测试我们的中心假设并实现本申请的目标：1）建立泰坦细胞在发病机制中的作用，以及2）鉴定参与泰坦细胞形成的信号通路。这项研究的预期成果是回答长期存在的问题，为什么信息素信号影响发病机制，在C。新生儿，以确定泰坦细胞生产对发病机制的影响，以确定导致泰坦细胞生产的信号，并了解泰坦细胞的形成和复制。这些结果将产生重要的积极影响，因为确定的信号传导组分和/或对泰坦细胞形成重要的下游靶点有望为艾滋病毒/艾滋病患者的预防和治疗干预提供新的靶点。我们希望我们的贡献是一个详细的了解如何信号转导级联调节泰坦细胞的形成和泰坦细胞的形成如何影响随后的细胞传播到中枢神经系统。这项研究意义重大，因为它有望提供有关泰坦细胞形成、调控和发病机制的知识，这将增强我们对隐球菌病基本要求的理解，并使泰坦细胞成为抗真菌治疗的靶点。

DESCRIPTION (provided by applicant): Pheromones and pheromone receptors have long been known to affect virulence of the opportunistic pathogen Cryptococcus neoformans, yet it is still entirely unclear how the biological ramifications of pheromone signaling affect pathogenesis. The Nielsen laboratory has shown that production of a newly characterized cell type - referred to as "titan cells" - is altered by pheromone sensing. Over-production of titan cells is correlated with reduced CNS penetration. The objective of this application is to define the role of titan cells in pathogenesis and how pheromone signaling alters titan cell production. The central hypothesis of our application is that the pheromone signaling cascade, in conjunction with other signaling components, regulates titan cell formation, which affects subsequent dissemination to the CNS. The rationale for the proposed research is that, once the role of titan cells in pathogenesis and how they are regulated is known, titan cell production can be targeted in new and innovative approaches for the prevention and treatment of cryptococcosis. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following specific aims: 1) Establish the role of titan cells in pathogenesis, and 2) Identify signaling pathways involved in titan cell formation. The expected outcomes of this research are to answer the long-standing question of why pheromone signaling affects pathogenesis in C. neoformans, to define the effect of titan cell production on pathogenesis, to identify signals that lead to titan cell production, and to understand titan cell formation and replication. Such results will have an important positive impact, because identified signaling components and/or downstream targets important for titan cell formation are expected to provide new targets for preventative and therapeutic interventions that will aid HIV/AIDS patients. We expect our contribution to be a detailed understanding of how signal transduction cascades regulate titan cell formation and how titan cell formation affects subsequent cell dissemination to the CNS. The proposed research is significant because it is expected to provide knowledge about titan cell formation, regulation, and pathogenesis that will enhance our understanding of the fundamental requirements for cryptococcal disease and allow titan cells to be targeted by antifungal therapy.