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

描述（由申请方提供）：新型隐球菌是细胞介导免疫缺陷患者发病和死亡的主要原因。本研究旨在探讨调控mRNA降解在C.新生儿在宿主体内存活并引发疾病总体假设是，Ccr4，mRNA降解机制的催化组分是耐热性和致病适应性的重要调节剂。第一个目标是评估Ccr4缺失对耐热性、致病性和mRNA降解的影响。目的2将确定Ccr4在细胞周期调控和复制应激反应中的作用，模拟宿主条件，包括巨噬细胞内的生长。第三个目标是确定促进Ccr4与另一种致病适应性调节因子Vad1在加工体（mRNA降解位点）中共定位的条件。这将确定条件下，Vad1和Ccr4协调和独立的功能，以应对压力。Ccr4是一个潜在的药物靶点，因为缺失会导致宿主温度下严重的生长缺陷。通过该途径调控的细胞过程和基因的鉴定具有鉴定新的治疗靶点的潜力，并将提供对C。新形虫能够适应宿主的压力环境并引起人类疾病。

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.