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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：
9000439
负责人：
Teresa R. OMeara
金额：
$ 0.79万
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/9000439
关键词：
Address Alleles Antifungal Agents Antifungal Therapy Area Biological Biology Candida albicans Chemicals Client Clinical Co-Immunoprecipitations Data Defect Development Disease Drug Targeting 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 Mass Spectrum Analysis Mediating Molecular Chaperones Monitor Morphogenesis Mycoses Pathogenesis Patients Pharmaceutical Preparations Phenotype Population Prevalence Process Proteins Proteomics Reproducibility Research Role Saccharomyces cerevisiae Signal Transduction Stress Structure Systemic infection Testing Tetracycline Control Therapeutic Time Transducers 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

Summary: Candida albicans is a leading human fungal pathogen that causes lifethreatening 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 targets for antifungal therapeutics and illuminate the mechanisms by which one of the most ancient and conserved cellular regulators governs fungal biology and disease.

简介: