Genomic analysis of Fungal Pathogenesis

真菌发病机制的基因组分析

• 批准号: 8711693
• 负责人: Vincent Michael Bruno
• 金额: $ 50.71万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711693
• 关键词: Animal Model; Antifungal Agents; Aspergillosis; Aspergillus; Beryllium; Biological Assay; Candida; Candida albicans; Candidiasis; Cells; Collection; Communicable Diseases; Communities; Complex; Data; Development; Disease; Disease Outcome; Functional RNA; Funding; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Generations; Genes; Genome; Genomics; Goals; Growth; Homologous Gene; Immune response; Immune system; Immunocompromised Host; Individual; Infection; Lead; Mammalian Cell; Mammals; Metabolic Pathway; MicroRNAs; Microbe; Modeling; Mucorales; Mucormycosis; Mus; Mycoses; Nature; North America; Organism; Outcome; Pathogenesis; Technology; Testing; Tissues; Transcript; Work; combat; comparative; deep sequencing; falls; follow-up; fungal genetics; fungus; gene function; genetic element; genome analysis; genome sequencing; human disease; in vivo; interest; microbiome; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; pathogen; response; therapeutic target; transcriptome sequencing; transcriptomics

There has been a dramatic rise in the number of severe fungal infections due to a constant rise in the number of individuals who are immunocompromised. Strong similarities in the basic eukaryotic metabolic pathways between fungi and mammalian cells have hindered the development of antifungal agents because many compounds that are effective at inhibiting fungal growth are also toxic to host cells. It is becoming clear that novel antifungal agents alone are unlikely to significantly reduce the mortality rate of fungal infections without the aid of new therapeutic approaches. One promising approach is to combine current antifungal treatments with agents that enhance the host immune system's ability to eliminate the microbe. Such an approach requires a detailed understanding of the complex interaction between host and pathogen. Infections due to Candida, Aspergillus, and Mucorales are the most common fungal infections that are associated with poor outcome. Together, these three phylogenetically and biologically distinct fungi are responsible for approximately 90% of the invasive fungal infections that occurred in North America between 2004 and 2008. Here we will combine dual-species RNA-seq, comparative genome analysis, well established animal models and fungal genetics to systematically and comprehensively analyze the host-pathogen interactions of these diverse fungal pathogens. Analyzing all three different types of fungi using the same approach will enable us to define commonalities as well as key differences among the organisms and the responses they elicit in the host. The proposed studies will provide a wealth of information regarding gene function and regulation in both the fungus and the host and will likely lead to the identification of novel therapeutic targets to treat this increasingly serious cause of human disease.

有一个急剧上升的数量严重的真菌感染由于不断上升， 免疫功能低下的人数。真核生物的基本代谢 真菌和哺乳动物细胞之间的通路阻碍了抗真菌剂的发展， 许多有效抑制真菌生长的化合物对宿主细胞也是有毒的。越来越清楚的 单独使用新型抗真菌药物不太可能显著降低真菌感染的死亡率 没有新的治疗方法的帮助。一种有希望的方法是将联合收割机 用增强宿主免疫系统消除微生物能力的药物治疗。这样的 这种方法需要对宿主和病原体之间复杂的相互作用有详细的了解。 念珠菌属、曲霉菌属和毛霉菌属的感染是最常见的真菌感染， 与不良结局相关。总之，这三种在遗传学和生物学上不同的真菌是 在北美，大约90%的侵袭性真菌感染是由这种真菌引起的。 2004年和2008年。在这里，我们将结合联合收割机双物种RNA-seq，比较基因组分析，以及建立 动物模型和真菌遗传学，以系统和全面地分析宿主-病原 这些不同的真菌病原体的相互作用。分析所有三种不同类型的真菌使用 同样的方法将使我们能够定义生物体之间的共性和关键差异， 它们在宿主中引起的反应。拟议的研究将提供大量信息， 基因的功能和调控在真菌和宿主，并可能导致新的鉴定 治疗目标，以治疗这一日益严重的人类疾病的原因。