Virulence gene discovery in Coccidioides

球孢子菌毒力基因的发现

基本信息

批准号：
10364967
负责人：
Anita Sil
金额：
$ 30.51万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364967
关键词：
Affect Area Arizona Biology California Candidate Disease Gene Carbon Dioxide Cells Central America Chemicals Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coccidioides Coccidioides immitis Coccidioides posadasii Coccidioidomycosis DNA Sequence Development Diagnostic Disease Disease Progression Dissection Drug Screening Event Genes Genetic Genome Genomics Growth Growth and Development function High temperature of physical object Hospital Costs Immune Immunocompetent Incidence Incubated Individual Infection Inhalation Laboratories Libraries Lung Mediating Methods Molecular Mutagenesis Nature Organism Pathogenesis Pathway interactions Pharmaceutical Preparations Phenotype Play Population Process Proteomics Public Health Publishing Reproduction spores Resolution Role Rupture Scientist Site Soil Source South America System Temperature Testing Variant Virulence Work clinical diagnostics density drug discovery drug repurposing experience fungus gene discovery gene function genome wide association study genome wide screen mutant new therapeutic target novel novel therapeutic intervention nuclear division pathogen pathogenic fungus pathogenic microbe small molecule therapeutic candidate tool trait transcription factor transcriptomics

项目摘要

Project 1 Summary: Virulence Gene Discovery in Coccidioides The focus of Project 1 is virulence gene discovery in Coccidioides. Despite the impact of Coccidioides infection, the molecular understanding of virulence mechanisms in this fungus is limited. Only a handful of Coccidioides genes have been implicated any virulence-relevant traits. Given the need to accelerate drug discovery and resolve the public health crisis posed by this fungus in the endemic areas, it is imperative to dissect virulence strategies used by Coccidioides to manipulate the host. Here we apply powerful systems-level tools to identify virulence-relevant genes. Such a landmark discovery effort will help open up the field at long last, providing a rich source of virulence genes to serve as new therapeutic targets. The ability of Coccidioides to cause disease depends on an elaborate developmental transition from saprophytic soil form to host form. Specifically, the hyphal form of the organism produces arthroconidia, which disperse easily and can be inhaled by mammalian hosts. Once inside the host lung, arthroconidia germinate, enlarge, and undergo nuclear division and segmentation to form large spherules filled with vegetative endospores. Rupture of the spherules allows release of endospores and dissemination of the fungus to other sites. Here we bring together a powerful team of scientists with expertise in the basic biology of thermally dimorphic fungi and statistical genetics, and in successful application of drug screens to target the growth and development of microbial pathogens, including fungi. Given the critical role of spherule development in disease progression, a major focus of this project is the genomic and genetic dissection of this process. We will identify candidate genes that govern spherulation by taking advantage of three complementary approaches: (1) Genome-wide association studies (GWAS); (2) high-resolution transcriptomics and proteomics of spherulation; and (3) drug repurposing to identify chemicals that inhibit spherulation and/or fungal growth. Taken together, these approaches will allow us to elucidate critical molecular events that take place during spherule development in the context of infection as well as identify new candidate therapeutics.

项目1摘要：球虫下毒力基因发现项目1的重点是球虫剂中的毒力基因发现。尽管有球孢子菌的影响感染，这种真菌中对毒力机制的分子理解是有限的。只有少数球球菌基因已被涉及与毒力相关的特征。鉴于需要加速药物发现并解决这种真菌在地方性地区造成的公共卫生危机，必须进行剖析球迪氏菌使用的毒力策略来操纵宿主。在这里，我们将强大的系统级工具应用于鉴定与毒力相关的基因。这样的具有里程碑意义的发现工作将有助于终于开放该领域，提供丰富的毒力基因来源，以作为新的治疗靶标。球球菌引起疾病的能力取决于从腐生土壤形式形式。具体而言，生物体的菌丝形式会产生节肢动物，这很容易分散，可以被哺乳动物宿主吸入。进入宿主的肺部后，节肢动物发芽，扩大并进行核部门和分割，形成充满植物的大型球形内孢子。球形破裂允许释放内生孢子并将真菌传播到其他站点。在这里，我们将一个强大的科学家团队汇集在一起，在热生物学基本生物学方面具有专业知识二态真菌和统计遗传学，以及成功地应用药物筛查以针对生长和包括真菌在内的微生物病原体的发展。鉴于球形发展在疾病中的关键作用该项目的主要重点是该过程的基因组和遗传解剖。我们将确定通过利用三种互补方法来控制领域的候选基因：（1）全基因组关联研究（GWAS）；（2）球形的高分辨率转录组学和蛋白质组学；（3）重新利用药物以识别抑制球体和/或真菌生长的化学物质。在一起，这些方法将使我们能够阐明球形发育过程中发生的关键分子事件在感染的背景下，并确定新的候选治疗疗法。