Virulence gene discovery in Coccidioides

球孢子菌毒力基因的发现

• 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
• 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

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.

项目一：球孢子菌属中毒力基因的发现 项目1的重点是发现球孢子菌的毒力基因。尽管球孢子菌的影响 感染，在这种真菌的毒力机制的分子理解是有限的。只有少数 球孢子菌基因与毒力相关性状有关。鉴于需要加速药物 为发现和解决该真菌在流行区造成的公共卫生危机， 球孢子菌操纵宿主的毒力策略。在这里，我们应用强大的系统级工具， 鉴定毒力相关基因。这样一个具有里程碑意义的发现努力将有助于最终打开这一领域， 提供了丰富的毒力基因来源以作为新的治疗靶点。 球孢子菌引起疾病的能力取决于一个复杂的发育转变， 腐殖土型到寄主型。具体地说，该生物体的菌丝形式产生节孢子， 易于分散，并可被哺乳动物宿主吸入。一旦进入宿主的肺，节孢子就会发芽， 扩大，并进行核分裂和分割，形成大小球充满营养 内生孢子小球体的破裂允许内生孢子的释放并将真菌传播到其他真菌中。 网站.在这里，我们汇集了一个强大的科学家团队，他们在热的基础生物学方面具有专业知识。 二型真菌和统计遗传学，并在成功应用药物筛选，以目标的增长和 微生物病原体的发展，包括真菌。鉴于小球发育在疾病中的关键作用 该项目的一个主要重点是这一过程的基因组和遗传解剖。我们将确定 候选基因通过利用三种互补方法来控制球形化：（1） 全基因组关联研究（GWAS）：（2）球形化的高分辨率转录组学和蛋白质组学; 和（3）药物再利用以鉴定抑制成球和/或真菌生长的化学物质。综合起来看， 这些方法将使我们能够阐明小球发育过程中发生的关键分子事件， 在感染的情况下，以及确定新的候选疗法。