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

基本信息

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
项目类别：
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

项目摘要

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）：新近加密赛是导致细胞介导的免疫缺陷患者发病率和死亡率的主要原因。这项研究提案旨在研究受调节的mRNA降解在新梭菌在宿主内生存并引起疾病的能力的作用。总体假设是CCR4是mRNA降解机械的催化成分是热耐耐受性和致病性适应性的重要调节剂。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。 AIM 2将确定CCR4在细胞周期调节中的作用以及在模仿宿主条件（包括巨噬细胞生长）的条件下对复制应力的反应。第三个目标旨在确定促进CCR4与另一个病原适应度VAD1的调节剂在加工体中（mRNA降解部位）进行的条件。这将确定VAD1和CCR4在应力下协同和独立的函数的条件。 CCR4是潜在的药物靶标，因为缺失会导致宿主温度下的严重生长缺陷。通过该途径调节的细胞过程和基因的这种鉴定具有鉴定新的治疗靶标的潜力，并将提供有关Neoformans C. Neoformans如何适应宿主的压力环境并引起人类疾病的洞察力。