Genomic and Transcriptomic Analysis of Invasive Fungal Pathogens

侵袭性真菌病原体的基因组和转录组分析

基本信息

批准号：
10597151
负责人：
Vincent Michael Bruno
金额：
$ 79.08万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597151
关键词：
Address Animal Model Antifungal Agents Antifungal Therapy Binding Biological Assay Biology CRISPR/Cas technology Candida auris Cells Chemotherapy-Oncologic Procedure Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communicable Diseases Communities Complex Data Data Set Development Disease Outcome Drug resistance Elements Family Gene Expression Regulation Genes Genetic Transcription Genome Genomic approach Genomics Goals Growth Immune response Immune system Immunocompromised Host Immunosuppressive Agents Individual Infection Invaded Investigation Knowledge Mammalian Cell Mediating Medical Metabolic Pathway Microbe Molecular Mucorales Mucormycosis Mycoses Nature Operative Surgical Procedures Organ Transplantation Organism Pathogenesis Patients Pharmaceutical Preparations Phylogenetic Analysis Prevalence Prevention strategy Resistance Resources Scedosporium Technology Testing The science of Mycology Therapeutic Tissues Transcript United States Untranslated RNA Vaccines Virulent Work clinically significant combat comparative comparative genomics deep sequencing design experimental study follow-up fungal genetics fungus gene function genetic analysis genetic element genome analysis high risk human disease in vivo insight interest mortality mouse model new therapeutic target novel novel strategies novel therapeutic intervention pathogen pathogenic fungus prevent rapid growth response therapeutic target transcriptome transcriptome sequencing transcriptomics treatment strategy whole genome

项目摘要

SUMMARY/ABSTRACT There has been a dramatic rise in the number of severe fungal infections due to a constant increase 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. Promising alternative approaches include combining current antifungal treatments with agents that enhance the host immune system's ability to eliminate the microbe or disrupt an interspecies molecular interaction that governs invasion. These approaches require a detailed understanding of the complex interaction between host and pathogen. This proposal will focus on three emerging fungal pathogens - Scedosporium spp, Candida auris and Mucorales fungi. Infections with these three phylogenetically distinct pathogens frequently fail to respond to currently available antifungal therapy and are therefore associated with extremely high mortality rates. Here we will combine dual-species RNA-seq, comparative genome analysis, established animal models and fungal genetics to systematically and comprehensively analyze the host-pathogen interactions for each class. 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.

摘要/摘要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。有希望的替代方法包括结合当前的使用增强宿主免疫系统消除微生物能力的药物进行抗真菌治疗，或破坏控制入侵的种间分子相互作用。这些方法需要详细的了解宿主和病原体之间复杂的相互作用。该提案将重点关注三个方面新出现的真菌病原体 - Scedosporium spp、耳念珠菌和毛霉目真菌。感染这些三种系统发育上不同的病原体经常无法对当前可用的抗真菌治疗做出反应，并且因此与极高的死亡率相关。这里我们将结合双物种RNA-seq，比较基因组分析、建立动物模型和真菌遗传学，以系统地和全面分析每个类别的宿主-病原体相互作用。分析所有三种不同类型使用相同的方法对真菌进行研究将使我们能够定义真菌之间的共同点以及关键差异生物体及其在宿主体内引起的反应。拟议的研究将提供丰富的信息关于真菌和宿主的基因功能和调控，可能会导致鉴定寻找新的治疗靶点来治疗这种日益严重的人类疾病。