Genomic analysis of Fungal Pathogenesis

真菌发病机制的基因组分析

基本信息

批准号：
9248251
负责人：
Vincent Michael Bruno
金额：
$ 50.08万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9248251
关键词：
Animal Model Antifungal Agents Aspergillosis Aspergillus Aspergillus fumigatus Biological Biological Assay Candida Candida albicans Candidiasis Cells Collection Communicable Diseases Communities Complex Data Development Disease Disease Outcome Elements Funding Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Genome Genomics Goals Growth Homologous Gene Immune response Immune system Immunocompromised Host Individual Infection Mammalian Cell Mammals Metabolic Pathway MicroRNAs Microbe Mucorales Mucormycosis Mycoses Nature North America Organism Outcome Pathogenesis Pathogenicity Phylogenetic Analysis Technology Testing Tissues Transcript Untranslated RNA Work combat comparative deep sequencing falls follow-up fungal genetics fungus gene function genetic analysis 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 transcriptome sequencing transcriptomics

项目摘要

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.

由于真菌感染的持续增加，严重真菌感染的数量急剧增加。免疫功能低下的个体数量。真核生物的基本代谢有很强的相似性真菌和哺乳动物细胞之间的通路阻碍了抗真菌药物的开发，因为许多能有效抑制真菌生长的化合物对宿主细胞也有毒。情况逐渐明朗单独使用新型抗真菌药物不太可能显着降低真菌感染的死亡率无需新的治疗方法的帮助。一种有前途的方法是将当前的抗真菌药物结合起来使用增强宿主免疫系统消除微生物能力的药物进行治疗。这样一个方法需要详细了解宿主和病原体之间复杂的相互作用。念珠菌、曲霉和毛霉菌引起的感染是最常见的真菌感染，与不良结果相关。这三种在系统发育和生物学上不同的真菌一起大约 90% 的侵袭性真菌感染是由这种真菌引起的。 2004年和2008年。这里我们将结合双物种RNA-seq，比较基因组分析，已经很好建立动物模型和真菌遗传学，系统、全面地分析宿主病原体这些不同真菌病原体的相互作用。使用以下方法分析所有三种不同类型的真菌同样的方法将使我们能够定义生物体和生物体之间的共性以及关键差异。它们在宿主体内引起的反应。拟议的研究将提供有关以下方面的大量信息：真菌和宿主中的基因功能和调控，可能会导致新的鉴定治疗这一日益严重的人类疾病的治疗目标。