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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.

项目摘要白色念珠菌是HIV/AIDS患者的重要机会致病菌，粘膜疾病如口咽念珠菌病（OPC）和食管念珠菌病（EC）。时代的抗逆转录病毒疗法（ART）、C.白色念珠菌仍然是最常见的真菌病原体， HIV/AIDS和OPC是HIV感染者中最常见的感染之一，免疫抑制（CD 4计数200-500）。OPC的发病机制可分为两个阶段：1） C.粘膜表面上的白色念珠菌粘附/生物膜形成和2）菌丝介导的粘膜表面的侵袭。上皮和粘膜下基质，伴有炎症和组织损伤。因此，OPC 其发病机制依赖于C.白色念珠菌毒力：粘附，生物膜形成，和形成。虽然这些因素中的每一个都已经用特定的C.白色突变体，没有系统的大规模的OPC发病机制的遗传分析已经进行。的目标本申请旨在定义和表征表达C.白色导致口腔疾病。最近，我们率先使用基于复杂单倍不足（CHI）的遗传学方法，互动分析，以了解复杂的遗传网络的功能。在这里，我们建议使用CHI 分析，以检验假设，Cbk 1代表转录过程的主要调节因子， OPC发病机制（目的1）。除了这种通路内分析，我们将进行第一次大规模的小鼠口腔念珠菌病（Aim 2）和体内所需TF网络的遗传筛选和CHI分析执行（目标3）。Aim 3中的筛选将利用我们的新型活体成像测定来定量地在小鼠的上皮下基质中区分酵母和丝状细胞。这个屏幕不仅是第一个在活体C.白色念珠菌筛选，但也将使我们能够区分所需的TF 粘附/生物膜形成阶段所需的TF的OPC侵入阶段。