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The Genetic Basis of Virulence in Cryptococcus Neoformans

新型隐球菌毒力的遗传基础

基本信息

批准号：
10658925
负责人：
JOSEPH HEITMAN
金额：
$ 58.28万
依托单位：
DUKE UNIVERSITY
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：
2017-07-05 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658925
关键词：
Affect Alleles Amoeba genus Animal Model Animals Antifungal Agents Basidiomycota Benign Biological Models Biology Cell model Cells Cellular Morphology Cessation of life Chemicals Chromosome Mapping Communities Complement Complex Cryptococcosis Cryptococcus Cryptococcus gattii Cryptococcus neoformans Cyclic AMP Cyclic AMP-Dependent Protein Kinases Disease Drug resistance Ecology Environment Etiology Event Evolution Exhibits Foundations Funding Fungal Drug Resistance Genes Genetic Genetic Determinism Genetic Epistasis Genetic Transcription Genetic Variation Genetic study Genomic approach Genotype High temperature of physical object Human Infection Invaded Maps Medical Methodology Morbidity - disease rate Morphology Organ Pathogenesis Pathogenicity Pathway interactions Pattern Phagocytes Phenotype Physiological Polysaccharides Population Prevention Public Health Quantitative Trait Loci Regulation Research Resources Shapes Signal Pathway Signal Transduction Sister System Testing Tissues Transcriptional Regulation Variant Virulence Yeasts capsule comparative fungus gene network genetic architecture genetic resource genetic variant genome resource insight member microbial microorganism interaction mortality novel novel strategies novel therapeutic intervention opportunistic pathogen pathogen pathogenic fungus tool trait

项目摘要

Abstract Pathogenic fungi of the genus Cryptococcus contribute to nearly 200,000 deaths annually world- wide. However, not all Cryptococcus isolates cause lethal infections; some are relatively benign whereas others are hypervirulent. Differences in pathogenicity are often correlated with variation in speciﬁc morphological and physiological features such as the ability to grow at high tempera- tures, the size of the protective polysaccharide capsule surrounding the yeast cell, or resistance to antifungal drugs. To advance the understanding of Cryptococcus biology and cryptococcal disease, we seek to identify genetic differences between isolates and species that lead to changes in viru- lence and virulence-related traits, to disentangle the effects of genetic variants on gene networks and pathways that govern such traits, and to understand the ecological interactions that contribute to pathogenesis. We propose to apply population and quantitative genomic approaches and microbial experi- mental evolution to dissect the genetic basis of variation in virulence and virulence-related traits in Cryptococcus. We propose three inter-related speciﬁc aims: Aim 1) Build mapping populations and carry out Quantitative Trait Locus (QTL) mapping in Cryptococcus neoformans, Cryptococcus deneofor- mans, and Cryptococcus gattii to identify genes and alleles that contribute to differences in virulence traits and resistance to anti-fungal drugs; Aim 2) Employ a novel chemical epistasis approach to dissect the impact of natural variation on signaling pathways and transcriptional networks that control virulence traits; and Aim 3) Utilize trait mapping and experimental evolution to identify genetic variants that modulate interactions between Cryptococcus and phagocytic amoeba and test whether these variants correlate with virulence in cellular and animal models of fungal disease.

抽象的隐球菌属致病真菌每年导致全世界近 20 万人死亡宽的。然而，并非所有隐球菌分离株都会引起致命的感染；有些是相对良性的而另一些则毒性很强。致病性的差异通常与变异相关特定的形态和生理特征，例如在高温下生长的能力结构，围绕酵母细胞的保护性多糖胶囊的大小，或对抗真菌药物。为了增进对隐球菌生物学和隐球菌疾病的了解，我们试图找出导致病毒变化的分离株和物种之间的遗传差异强度和毒力相关特征，以理清遗传变异对基因网络的影响以及控制这些特征的途径，并了解有助于的生态相互作用至发病机制。我们建议应用群体和定量基因组方法以及微生物经验心理进化来剖析毒力变异的遗传基础和毒力相关特征隐球菌。我们提出了三个相互关联的具体目标：目标 1) 绘制人口图并在新型隐球菌、新隐球菌中进行数量性状位点（QTL）作图人类和格特隐球菌鉴定导致毒力差异的基因和等位基因性状和抗真菌药物耐药性；目标 2) 采用一种新颖的化学上位方法剖析自然变异对信号通路和转录网络的影响控制毒力特征；目标 3) 利用性状作图和实验进化来识别调节隐球菌和吞噬阿米巴原虫之间相互作用的遗传变异和测试这些变异是否与真菌疾病细胞和动物模型中的毒力相关。