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Mechanisms of Fluconazole-Induced Aneuploidy in Cryptococcus Neoformans

氟康唑诱导新型隐球菌非整倍体的机制

基本信息

批准号：
8957277
负责人：
Lukasz Kozubowski
金额：
$ 43.72万
依托单位：
CLEMSON UNIVERSITY
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：
2015-06-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8957277
关键词：
Acquired Immunodeficiency Syndrome Address Affect Aneuploidy Architecture Ascomycota Azole resistance Basidiomycota Biochemical Biological Models Biology Cause of Death Cell Fraction Cell division Cells Cellular biology Central Nervous System Diseases Central Nervous System Fungal Infections Cessation of life Chromosomes Cryptococcal Meningitis Cryptococcus neoformans Cryptococcus neoformans infection Diploidy Disease Drug resistance Ergosterol Eukaryota Event Exposure to Fission Yeast Flow Cytometry Fluconazole Fluconazole resistance Fluorescence Microscopy Gene Dosage Generations Genetic Models Genome Goals Health Human Immune response Immunocompetent Immunocompromised Host In Vitro Infection Laboratories Learning Lung Meiosis Microscopy Mitotic Mitotic Checkpoint Modeling Molecular Molecular Biology Morbidity - disease rate Organism Pathogenicity Pathway interactions Pharmaceutical Preparations Ploidies Polyploidy Population Production Proteins Public Health Reporter Reporting Research Resolution Role Saccharomyces cerevisiae Saccharomycetales Series Students System Techniques Testing Virulent Work Yeasts base cell growth effective therapy experience fungus graduate student human disease improved in vivo nuclear division pathogen public health relevance resistance gene response segregation tool undergraduate student

项目摘要

DESCRIPTION (provided by applicant): Fungi are an increasingly important cause of death and morbidity in both immunocompetent and immunocompromised patients. Cryptococcal meningitis caused by Cryptococcus neoformans is the most common cause of fungal central nervous system infection in the world. One million cases of Cryptococcal infection occur globally, largely in the context of AIDS and constitute one-third of all AIDS-associated deaths. Despite these public health threats, effective treatments for cryptococcosis are inadequate. Recent reports indicate a high importance of genome plasticity in the pathogenicity of C. neoformans. For example, changes in chromosomal copy number are a major factor contributing to the resistance to the azole drug fluconazole in vitro and in vivo. The list of key resistance genes whose copy number increases in fluconazole-resistant C. neoformans isolates is well established. However, very little is known about the molecular mechanisms that govern changes in chromosomal copy number in this organism. The main objective of this proposal is to elucidate mechanisms responsible for generation of aneuploidy when C. neoformans is exposed to fluconazole. We will perform a detailed analysis of the effects of fluconazole on cell growth and nuclear division. In addition, we will elucidate basic architecture of the spindle assembly checkpoint (SAC) pathway in C. neoformans, and explore the possibility that the inhibition of this pathway is one of the causes of fluconazole-triggered aneuploidy leading to drug resistance. This work will contribute to our understanding of the mechanisms that are involved in chromosomal changes of a fungal pathogen during infection. This project will engage graduate and undergraduate students and allow for hands-on research experience. Students will be exposed to various laboratory techniques and will learn formulating and testing research hypotheses.

描述（由申请方提供）：真菌是免疫功能正常和免疫功能低下患者死亡和发病的重要原因。由新型隐球菌引起的隐球菌性脑膜炎是世界上最常见的真菌性中枢神经系统感染。全球有100万隐球菌感染病例，主要是在艾滋病的背景下发生的，占所有艾滋病相关死亡的三分之一。尽管存在这些公共卫生威胁，但对隐球菌病的有效治疗是不够的。最近的研究表明，基因组可塑性在C.新人类例如，染色体拷贝数的变化是导致体外和体内对唑类药物氟康唑耐药性的主要因素。在抗氟康唑的C.新形式的分离株是公认的。然而，很少有人知道的分子机制，在这种生物体中的染色体拷贝数的变化。本研究的主要目的是阐明C.新生儿暴露于氟康唑。我们将详细分析氟康唑对细胞生长和核分裂的影响。此外，我们将阐明梭菌纺锤体组装检查点（SAC）途径的基本结构。新形式的，并探讨该途径的抑制是氟康唑触发的非整倍体导致耐药性的原因之一的可能性。这项工作将有助于我们了解真菌病原体在感染过程中染色体变化的机制。该项目将吸引研究生和本科生，并允许动手研究经验。学生将接触到各种实验室技术，并将学习制定和测试研究假设。