Global analysis of Hsp90 client proteins in Candida albicans

白色念珠菌中 Hsp90 客户蛋白的整体分析

基本信息

批准号：
8832127
负责人：
Teresa R. OMeara
金额：
$ 4.46万
依托单位：
UNIVERSITY OF TORONTO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-03 至 2018-02-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8832127
关键词：
Address Alleles Antifungal Agents Antifungal Therapy Area Biological Biology Candida albicans Chemicals Client Clinical Co-Immunoprecipitations Data Defect Development Disease Drug resistance Engineering Filament Foundations Geldanamycin Gene Targeting Genetic Genetic Epistasis Genome Genomic approach Goals Growth Heat-Shock Proteins 90 Homeostasis Human Hypersensitivity Immunocompromised Host In Vitro Individual Infection Invertebrates Investigation Knowledge Libraries Life Mass Spectrum Analysis Modeling Molecular Chaperones Monitor Morphogenesis Pathogenesis Pharmaceutical Preparations Phenotype Physical Chromosome Mapping Proteins Proteomics Reproducibility Research Resistance development Role Saccharomyces cerevisiae Signal Transduction Stress Structure Systemic infection Testing Tetracyclines Therapeutic Time Transducers Tweens Virulence Work Yeast Model System Yeasts base biological adaptation to stress inhibitor/antagonist mutant novel pathogen promoter protein activation public health relevance research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Candida albicans is a leading human fungal pathogen that causes life-threatening systemic infections, especially in immunocompromised individuals. Targeting the Hsp90 chaperone protein provides a powerful therapeutic strategy for fungal disease. However, clinical utility depends upon identifying components of the Hsp90 network that can be selectively targeted in the pathogen without harming the infected host. A combination of proteomic and chemical genomic approaches will provide the first global analysis of the Hsp90 chaperone network in C. albicans. This will test the hypothesis that Hsp90 and its co-chaperones interact with different client proteins under specific environmental conditions, enabling a range of adaptive responses that allow for virulence. Since Hsp90 is a central hub for protein homeostasis, the proposed research will identify Hsp90 interactors with important roles in stress response, drug resistance, morphogenesis, and virulence. These interactors will be prioritized based on: 1) identification in multiple screens; 2) magnitude and reproducibility of the genetic interaction or mutant phenotype; and 3) novelty of the interaction. All physical interactions will be validated by reciprocal co-immunoprecipitation, and all genetic interactions or morphogenetic defects will be validated by complementation with the wild-type allele. Epistasis analysis will determine the structure of the Hsp90 genetic network. Finally, the candidate targets will be evaluated for their role in virulence. This work will reveal novel target for antifungal therapeutics and illuminate the mechanisms by which one of the most ancient and conserved cellular regulators governs fungal biology and disease.

描述（由适用提供）：白色念珠菌是一种领先的人类真菌病原体，会导致威胁生命的全身感染，尤其是在免疫功能低下的个体中。靶向HSP90链酮蛋白为真菌疾病提供了强大的治疗策略。但是，临床实用性取决于鉴定可以选择在病原体而不会损害感染宿主的HSP90网络的组件。蛋白质组学和化学基因组方法的结合将提供白色念珠菌中HSP90链酮网络的首次全局分析。这将检验以下假设：在特定的环境条件下，HSP90及其同伴与不同客户蛋白相互作用，从而实现了允许病毒的一系列适应性反应。由于HSP90是蛋白质体内稳态的中心枢纽，因此拟议的研究将在压力反应，耐药性，形态发生和病毒中识别具有重要作用的HSP90相互作用。这些相互作用者将根据以下方面的优先级优先级：1）在多个屏幕中的识别； 2）幅度和可重复性遗传相互作用或突变表型； 3）互动的新颖性。所有物理相互作用将通过相互共免疫沉淀来验证，所有遗传相互作用或形态发生缺陷将通过野生型等位基因完成来验证。上毒分析将确定HSP90遗传网络的结构。最后，将评估候选目标在病毒中的作用。这项工作将揭示抗真菌治疗的新颖靶标，并阐明最古老，保守的细胞调节剂之一控制真菌生物学和疾病的机制。