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

• 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
• 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

 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（由申请人提供）：真菌是免疫功能正常和免疫功能低下患者死亡和发病的一个日益重要的原因。由新型隐球菌引起的隐球菌脑膜炎是世界上一百万例隐球菌感染的最常见原因。尽管存在这些公共卫生威胁，但感染在全球范围内发生，主要是在艾滋病背景下，占所有艾滋病相关死亡的三分之一。最近的报告表明，基因组可塑性对于新型隐球菌的致病性非常重要，例如，染色体拷贝数的变化是导致对唑类药物氟康唑的体外和体内耐药性的主要因素。在氟康唑耐药的新型隐球菌分离株中拷贝数增加的关键耐药基因的机制已得到充分证实，然而，人们对控制该生物体染色体拷贝数变化的分子机制知之甚少。该提案的主要目的是阐明当新型隐球菌接触氟康唑时产生非整倍体的机制。我们将对氟康唑对细胞生长和核分裂的影响进行详细分析。此外，我们将阐明基本结构。新型梭菌中纺锤体组装检查点（SAC）途径的影响，并探讨该途径的抑制是否是氟康唑触发的非整倍性导致的原因之一的可能性这项工作将有助于我们了解感染过程中真菌病原体染色体变化的机制。该项目将吸引研究生和本科生，并让学生获得实践研究经验。技术并将学习制定和测试研究假设。

项目成果

Fluconazole-Induced Ploidy Change in Cryptococcus neoformans Results from the Uncoupling of Cell Growth and Nuclear Division.

氟康唑诱导的新型隐球菌倍性变化是细胞生长和核分裂解偶联的结果。

• 发表时间: 2017
• 影响因子: 4.8
• 作者: Altamirano, Sophie;Fang, Diana;Simmons, Charles;Sridhar, Shreyas;Wu, Peipei;Sanyal, Kaustuv;Kozubowski, Lukasz
• 通讯作者: Kozubowski, Lukasz