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

• 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
• 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

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.

总结： 白色念珠菌是一种主要的人类真菌病原体， 全身性感染，尤其是免疫功能低下的个体。靶向 Hsp 90伴侣蛋白为真菌感染提供了一种有效的治疗策略， 疾病然而，临床实用性取决于鉴定Hsp 90的组分， 可以选择性地针对病原体而不伤害感染者的网络 主持人 蛋白质组学和化学基因组学方法的结合将提供第一个 对C.白色念珠菌这将考验 假设Hsp 90及其辅助分子伴侣与不同的客户蛋白相互作用， 特定的环境条件，使一系列的适应性反应，允许 毒性。 由于Hsp 90是蛋白质稳态的中心枢纽，因此拟议的研究将 鉴定在应激反应、耐药性 形态发生和毒性。这些互动者的优先次序将基于：1） 在多个屏幕上识别; 2）遗传的大小和再现性 相互作用或突变表型;和3）相互作用的新奇。所有物理 相互作用将通过相互免疫共沉淀来验证，并且所有的遗传 相互作用或形态发生缺陷将通过与 野生型等位基因。上位性分析将确定Hsp 90基因的结构， 网络最后，将评价候选靶标在毒力中的作用。这 这项工作将揭示抗真菌治疗的新靶点， 最古老和保守的细胞调节因子之一， 生物学和疾病