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：
9901444
负责人：
Vincent Michael Bruno
金额：
$ 53.65万
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/9901444
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 Foundations Gene Expression Regulation Genes Genetic Transcription Genome Genomic approach Genomics Goals Growth Ice Immune response Immune system Immunocompromised Host Immunosuppressive Agents Individual Infection 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 Structure Technology Testing The science of Mycology Therapeutic Tissues Transcript United States Untranslated RNA Vaccines Virulent Work base 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/摘要由于不断增加，严重真菌感染的数量急剧增加免疫功能低下的个体数量。基本真核代谢的强烈相似之处真菌和哺乳动物细胞之间的途径阻碍了抗真菌剂的发展，因为许多有效抑制真菌生长的化合物也对宿主细胞有毒。它变得清晰仅这种新型抗真菌剂就不太可能显着降低真菌感染的死亡率没有新的治疗方法。有希望的替代方法包括结合电流抗真菌治疗的药物可以增强宿主免疫系统消除微生物或破坏控制入侵的种间分子相互作用。这些方法需要详细了解宿主与病原体之间的复杂相互作用。该提议将重点放在三个新兴的真菌病原体 - Scedosporium spp，念珠菌和粘膜真菌。这些感染三种系统发育不同的病原体经常无法应对当前可用的抗真菌疗法和因此，与极高的死亡率有关。在这里，我们将结合双物种RNA-Seq，比较基因组分析，建立的动物模型和真菌遗传学对系统和真菌遗传学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的使用相同方法的真菌将使我们能够定义共同点以及关键差异生物体及其在宿主中产生的反应。拟议的研究将提供大量信息关于真菌和宿主的基因功能和调节，可能会导致识别新的治疗靶标，以治疗这种日益严重的人类疾病原因。