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Complex haploinsufficiency based genetic analysis of C. albicans pathogenesis

基于复杂单倍体不足的白色念珠菌发病机制的遗传分析

基本信息

批准号：
10300444
负责人：
Damian J Krysan
金额：
$ 41.51万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300444
关键词：
ACE2 AIDS/HIV problem Adhesions Affect Azole resistance BCR gene Bar Codes Biological Assay CD4 Lymphocyte Count Candida albicans Candidiasis Cells Complex Consensus Cyclic AMP-Dependent Protein Kinases Development Disease Epithelial Esophagus Filament Gene Expression Profile Genes Genetic Genetic Screening Genetic Transcription Genetic study Goals HIV Hyphae Immunosuppression In Vitro Infection Inflammation Libraries Mediating Mediator of activation protein Microbial Biofilms Molecular Morphogenesis Mouth Diseases Mucous Membrane Mus Mutation Oral candidiasis Pathogenesis Pathway Analysis Pathway interactions Patients Persons Pharmaceutical Preparations Phenotype Phosphorylation Site Phosphotransferases Plasmids Process Public Health Regulation Resources Signal Pathway Surface Testing Tissues Transcription Process Virulence Yeasts antiretroviral therapy base clinically significant compliance behavior deletion library gene function genetic analysis in vivo intravital imaging mouse model mutant novel novel therapeutic intervention opportunistic pathogen oropharyngeal thrush pathogenic fungus screening transcription factor

项目摘要

PROJECT SUMMARY Candida albicans is an important opportunistic pathogen for people living with HIV/AIDS and primarily causes mucosal diseases such as oropharyngeal candidiasis (OPC) and esophageal candidiasis (EC). In the era of antiretroviral therapy (ART), C. albicans remains the most common fungal pathogen affecting those with HIV/AIDS and OPC is one of the most common infections in HIV patients with mild-to-moderate immunosuppression (CD4 counts 200-500). The pathogenesis of OPC can be separated into two stages: 1) C. albicans adhesion/biofilm formation on the mucosal surface and 2) hyphae-mediated invasion of the epithelium and submucosal stroma with concomitant inflammation and tissue damage. Thus, OPC pathogenesis is dependent on three of the most important mediators of C. albicans virulence: adhesion, biofilm formation, and filamentation. Although each of these factors has been studied using specific C. albicans mutants, no systematic large-scale genetic analysis of OPC pathogenesis has been undertaken. The goal of this application is to define and characterize the transcriptional networks that underlay the ability of C. albicans to cause oral disease. Recently, we have pioneered the use of complex haploinsufficiency (CHI)-based genetic interaction analysis to understand the function of complex genetic networks. Here, we propose to use CHI analysis to test the hypothesis that Cbk1 represents a master regulator of transcriptional processes critical for OPC pathogenesis (Aim 1). In addition to this intra-pathway analysis, we will perform the first large-scale genetic screens for, and CHI analyses of, TF networks required for murine oral candidiasis (Aim 2) and in vivo filamentation (Aim 3). The screen in Aim 3 will utilize our novel intra-vital imaging assay to quantitatively differentiate between yeast and filamentous cells in the sub-epithelial stroma of mice. This screen will not only be the first in vivo C. albicans filamentation screen but also will allow us to distinguish TFs required for the invasion stage of OPC from TFs required for the adhesion/biofilm formation stage.

项目总结