The Candida albicans commensal program

白色念珠菌共生计划

基本信息

批准号：
8424206
负责人：
SUZANNE M NOBLE
金额：
$ 23.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8424206
关键词：
Accounting Affect Area Behavior Blood Circulation Candida Candida albicans Cell Surface Proteins Cells Collection Diploidy Disease Disseminated candidiasis Epigenetic Process Failure Gastrointestinal tract structure Gene Deletion Genes Genetic Programming Genetic Screening Genetic Transcription Hospitals Host Defense Human Human Microbiome Infection Iron Lead Leukocytes Libraries Life Style Mediating Mediator of activation protein Modality Modeling Molecular Mus Mycoses Organism Pathway interactions Patients Phase Phenotype Pilot Projects Play Prevention Prevention therapy Public Health Research Role Sepsis Source Sphingolipids Symbiosis Syndrome Testing Transcription Coactivator Virulence Virulence Factors Yeasts activating transcription factor base fitness fungus gastrointestinal gastrointestinal infection genetic resource improved in vivo microbial mouse model mutant novel pathogen programs screening transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): We seek to understand the molecular mechanisms of commensalism in Candida albicans, a normal component of the human microbiome as well as the most common cause of devastating fungal infections. Studies of C. albicans strains recovered from patients with Candida disease syndromes have demonstrated that the vast majority of disseminated infections arise from patients' own commensals (Odds et al., 2006). However, we have scant understanding of the molecular basis of commensalism or the commensal-to-pathogen transition. We recently generated two large collections of more than 750 homozygous gene deletion mutants of this obligate diploid organism (Homann et al., 2009) (Noble et al., 2010). By means of a genetic screen of the mutants in a mouse model of bloodstream infection, we identified multiple novel virulence factors including a fungal-specific sphingolipid (Noble et al., 2010) and a novel transcriptional activator of iron uptake genes (Chen, Pande et al., submitted). We now propose to use the same genetic resource to screen for commensalism factors in a mouse model of gastrointestinal commensalism. To this end, our pilot studies have already revealed a novel opaque- independent role for master regulator of the white-to-opaque phenotypic transition, Wor1, in promoting commensal infections of the gut. We hypothesize that C. albicans possesses distinct genetic programs for commensalism and virulence, and comparison of the results from the commensalism and virulence screens will directly test this hypothesis. The results will significantly enhance an understudied area research and promise to reveal opportunities for prevention and treatment of highly morbid of C. albicans infections.

描述（由申请人提供）：我们试图了解白色念珠菌共生的分子机制，白色念珠菌是人类微生物组的正常组成部分，也是毁灭性真菌感染的最常见原因。对从念珠菌病综合征患者体内回收的白色念珠菌菌株的研究表明，绝大多数播散性感染源自患者自身的共生菌（Odds 等，2006）。然而，我们对共生现象或共生体向病原体转变的分子基础知之甚少。我们最近生成了两个大型集合，其中包含这种专性二倍体生物的 750 多个纯合基因缺失突变体（Homann 等人，2009）（Noble 等人，2010）。通过对血流感染小鼠模型中的突变体进行遗传筛选，我们鉴定了多种新型毒力因子，包括真菌特异性鞘脂（Noble 等人，2010）和铁摄取基因的新型转录激活剂（Chen，Pande）等人提交）。我们现在建议使用相同的遗传资源来筛选胃肠共生小鼠模型中的共生因子。为此，我们的初步研究已经揭示了白色到不透明表型转变的主调节器 Wor1 在促进肠道共生感染中的一种新的不透明独立作用。我们假设白色念珠菌拥有独特的共生性和毒力遗传程序，共生性和毒力筛选结果的比较将直接检验这一假设。这些结果将显着加强尚未研究的领域的研究，并有望揭示预防和治疗高发病率白色念珠菌感染的机会。