Virulence gene discovery in Coccidioides

项目1综述：球孢子虫毒力基因的发现 项目1的重点是在球孢子虫中发现毒力基因。尽管球孢子虫的影响 但是，目前对该真菌致病机制的分子水平了解还很有限。只有少数几个 球孢子虫的基因已经牵涉到任何与毒力相关的特征。考虑到需要加速药物 发现和解决该真菌在流行区造成的公共卫生危机，解剖势在必行 球孢子虫用来操纵寄主的毒力策略。在这里，我们将强大的系统级工具应用于 鉴定毒力相关基因。这种里程碑式的发现努力最终将有助于打开这一领域， 提供了丰富的毒力基因来源，作为新的治疗靶点。 球孢子虫致病的能力取决于一种复杂的发育转变 腐生土壤由腐生土壤向寄主土壤转化。具体地说，该生物体的菌丝体产生节孢子，这是 易分散，可被哺乳动物宿主吸入。一旦进入宿主肺，节孢子就会萌发， 放大，进行核分裂和分割，形成充满营养物质的大球体 内生孢子。球体的破裂可以释放内孢子并将真菌传播给其他真菌。 网站。在这里，我们汇聚了一支强大的科学家团队，他们拥有热能生物基础生物学方面的专业知识。 二相性真菌和统计遗传学，并在成功应用药物筛选靶向生长和 微生物病原体的发展，包括真菌。鉴于球体发育在疾病中的关键作用 进展，这个项目的一个主要焦点是这一过程的基因组和基因解剖。我们将确定 利用三种互补方法控制球体形成的候选基因：(1) 全基因组关联研究；(2)球化的高分辨率转录组学和蛋白质组学； 以及(3)药物再利用，以确定抑制球状和/或真菌生长的化学物质。加在一起， 这些方法将使我们能够阐明球体发育过程中发生的关键分子事件。 在感染的背景下，以及确定新的候选疗法。

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.