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

Ccr4 在维持新型隐球菌的耐热性和致病性中的作用

• 批准号: 7261535
• 负责人: John C Panepinto
• 金额: $ 15.74万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261535
• 关键词: Africa; Aminoglycoside Antibiotics; Antifungal Agents; Area; Attenuated; Biological Assay; Boxing; Brain; Candidate Disease Gene; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell physiology; Cellular Immunity; Characteristics; Chimeric Proteins; Communities; Condition; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; DNA Damage; DNA Repair Gene; Data; Defect; Disease; Drug Delivery Systems; ERCC3 gene; Encephalitis; Environment; Exhibits; Flucytosine; Fluorouracil; Framycetin Sulfate; Future; Goals; Growth; HIV; Harvest; Human; Immune; Infection; Investigation; Kinetics; Lead; Life; Localized; Lung; Maintenance; Measurement; Measures; Meningitis; Messenger RNA; Microarray Analysis; Modeling; Morbidity - disease rate; Mus; Mutation; Northern Blotting; Nutrient; Organism; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagosomes; Pharmaceutical Preparations; Phenanthrolines; Phenotype; Plague; Ploidies; Predisposition; Process; Processed Genes; Proliferating; Protein Overexpression; Proteins; RNA Helicase; RNA Interference; Range; Regulation; Regulator Genes; Research; Research Personnel; Research Proposals; Role; Signal Transduction; Site; Southeastern Asia; Starvation; Stress; Syndrome; Systemic infection; Temperature; Testing; Time; Transcript; Up-Regulation; Virulence; Work; antiretroviral therapy; biological adaptation to stress; c-myc Genes; career; design; fitness; fungus; human disease; hydroxyurea; insight; mRNA Stability; mRNA Transcript Degradation; mRNA decapping; macrophage; mortality; mutant; novel; novel therapeutics; pandemic disease; pathogen; programs; reconstitution; research study; response; therapeutic target; tool; trait

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.

描述（由申请人提供）：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。本研究计划旨在研究受调控的mRNA降解在C. neoformans在宿主内存活和致病的能力中的作用。总的假设是，mRNA降解机制的催化成分Ccr4是耐热性和致病性适应度的重要调节因子。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（包括巨噬细胞内生长）的细胞周期调节和对复制应激的反应中的作用。第三个目标是确定促进Ccr4与另一个致病适应性调节因子Vad1在加工体（mRNA降解部位）共定位的条件。这将确定Vad1和Ccr4在应激反应中协调和独立发挥作用的条件。Ccr4是一个潜在的药物靶点，因为在宿主温度下缺失Ccr4会导致严重的生长缺陷。通过这一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，并将为了解新形梭菌如何能够适应宿主的应激环境并引起人类疾病提供见解。