Ccr4 in the maintenance of thermotolerance and pathogenicity of C. neoformans

描述(由申请人提供)：新生隐球菌是细胞免疫缺陷患者发病和死亡的主要原因。这项研究计划着手研究调节的信使核糖核酸降解在新生梭菌在宿主内存活和致病的能力中的作用。总体假设是，CCR4是mRNA降解机制的催化成分，是耐热性和致病适应性的重要调节因子。第一个目的是评估CCR4缺失对耐热性、致病性和mRNA降解的影响。目的2将确定CCR4在模拟宿主条件下的细胞周期调节和对复制应激的反应中的作用，包括巨噬细胞内的生长。第三个目标是确定促进CCR4与另一种致病适合性调节因子Vad1在加工体内共定位的条件，这是mRNA降解的部位。这将确定Vad1和CCR4在何种条件下协调独立地对压力做出反应。CCR4是一个潜在的药物靶点，因为缺失会导致宿主温度下的严重生长缺陷。这种对细胞过程和通过这一途径调控的基因的识别有可能识别新的治疗靶点，并将为了解新生葡萄球菌如何能够适应宿主的应激环境并导致人类疾病提供洞察。

DESCRIPTION (provided by applicant): Cryptococcus neoformans is a major cause of morbidity and mortality in patients with defects in cell mediated immunity. This research proposal sets out to investigate the role of regulated mRNA degradation in the ability of C. neoformans to survive within the host and cause disease. The overall hypothesis is that Ccr4, the catalytic component of the mRNA degradation machinery is an important regulator of thermotolerance and pathogenic fitness. The first aim sets out to assess the effect of Ccr4 deletion on thermotolerance, pathogenicity and mRNA degradation. Aim 2 will determine the role of Ccr4 in cell cycle regulation and response to replication stress under conditions that mimic conditions in the host including growth within macrophages. The third aim sets out to identify conditions that promote colocalization of Ccr4 with another regulator of pathogenic fitness, Vad1, in processing bodies, the site of mRNA degradation. This will identify conditions under which Vad1 and Ccr4 function coordinately and independently in response to stress. Ccr4 is a potential drug target, as deletion results in a severe growth defect at host temperature. This identification of cellular processes and genes regulated through this pathway has the potential for identification of novel therapeutic targets, and will provide insight into how C. neoformans is able to adapt to the stressful environment of the host and cause human disease.