Coccidioidomycosis:Genome Comparison, Selection and Transcription.

球孢子菌病：基因组比较、选择和转录。

• 批准号: 7608670
• 负责人: JOHN W. TAYLOR
• 金额: $ 38.79万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608670
• 关键词: Accounting; American; Area; Ascomycota; Aspergillus nidulans; Basidiomycota; Biology; Blastomyces; Candida; Candidate Disease Gene; Coca; Coccidioides; Coccidioides immitis; Coccidioidomycosis; Collaborations; Computer Simulation; Cryptococcus; Development; Disabled Persons; Disease; Evolution; Freezing; Gene Expression; Gene Pool; Genes; Genetic Transcription; Genetic Variation; Genome; Genomics; Goals; Harvest; Histoplasma; Human; Immunity; In Vitro; Infection; Knock-out; Laboratories; Laboratory Study; Life; Mammals; Methods; Molecular; Mus; Natural Selections; Neurospora crassa; Oligonucleotide Microarrays; Paracoccidioides; Pathogenicity; Pharmacologic Substance; Phase; Phenotype; Pneumocystis; Population; Prevention; Proteins; Public Health; Publishing; Race; Relative (related person); Research; Research Personnel; Saccharomyces; Silicon Dioxide; Testing; Tissues; Upper arm; Vaccination; Vaccines; Variant; Virulence; Virulence Factors; Wild Type Mouse; comparative; design; fungus; geographic population; in vivo; interest; laser capture microdissection; member; pathogen; prevent; tool

DESCRIPTION (provided by applicant): Our long-term objective is to develop methods to prevent and treat coccidioidomycosis, a systemic fungal disease of otherwise healthy humans caused by the fungi Coccidioides immitis and Coccidioides posadasii. The collaborating investigators are John Taylor and Garry Cole, directors of laboratories that study Coccidioides molecular developmental and evolutionary biology, respectively. Our goal in this proposal is to focus the tools of comparative genomics and gene expression on Coccidioides to identify genes important to pathogenicity and virulence. Two of our findings underlie our proposal: 1) disruption of genes known to be important to the pathogenicity of Coccidioides reduces its virulence in mammals, and 2) Coccidioides shows genetic variation among five geographic populations. The availability of complete, annotated genomes of each /coccidioides species and the genome of their non-pathogenic relative, Uncinocarpus reesii, is a major pillar of support for our project. We can greatly increase the number of targets for therapy or prevention by searching the genome for pathogenicity genes, while accounting for natural variation. We will evaluate our hypotheses about these genes by virulence tests in mice. Our specific aims are to: identify genes unique to Coccidioides as compared to Uncinocarpus, identify genes that show positive selection between Coccidioides species and compared to Uncinocarpus, and identify genes in Coccidioides with significant transcription differences between the saprobic and parasitic phases, both in vitro and in vivo. From this cadre of unique genes which are under positive selection and upregulated during the parasitic phase, we will identify a pool of putative pathogenicity genes that can we will test by assessing virulence in mice of the wild-type strain, the WT strain in which the gene of interest has been knocked out, and the KO strain with the gene of interest replaced. Via existing collaboration, our laboratories have studied and published on natural selection of Coccidioides pathogenicity genes and assessed transcription in the saprobic and parasitic phases. Relevance to public health: Nearly 10% of Americans live in areas endemic to coccidioidomycosis, and approximately 5% of those infected develop life-threatening disease. Symptomatic infections confer long term immunity, so vaccination is possible. Likewise, virulence is reduced when pathogenicity genes are disabled, which indicates that pharmaceutical targeting of these gene products should be efficacious.

描述（由申请人提供）：我们的长期目标是开发预防和治疗球虫菌病的方法，这是一种由真菌coccidioides Immisis和coccidioides posadasii引起的健康人类的全身真菌疾病。合作的研究人员是分别研究球虫分子发育和进化生物学的实验室主任约翰·泰勒（John Taylor）和加里·科尔（Garry Cole）。我们在该提案中的目标是将比较基因组学和基因表达的工具集中在球虫下，以鉴定对致病性和毒力重要的基因。我们的提议的基础是我们的两个基础：1）对球虫剂的致病性很重要的基因的破坏降低了其在哺乳动物中的毒力，而2）球虫剂在五个地理种群中显示出遗传变异。每种 /球虫种类的完整，带注释的基因组的可用性以及其非致病性相关REESII的基因组，是对我们项目的支持的主要支柱。我们可以通过搜索基因组的致病性基因来大大增加治疗或预防靶标的数量，同时考虑自然变异。我们将通过小鼠的毒力测试评估有关这些基因的假设。我们的具体目的是：与未含量相比，鉴定球虫剂独有的基因，鉴定出在球虫剂中表现出阳性选择的基因，并与coccidioides相比，并鉴定在腐生和寄生虫相之间具有显着转录差异的球虫菌中的基因，包括在内，包括腐生和寄生虫相。从这个独特基因的干部中，我们将在寄生阶段进行积极选择并上调，我们将确定一个假定的致病性基因库，我们可以通过评估野生型菌株小鼠的毒力来测试，野生型菌株的毒力，该WT菌株已淘汰了感兴趣的基因，并与感兴趣的基因替换了KO菌株。通过现有的合作，我们的实验室研究并发表了有关球虫的自然选择，并评估了腐生和寄生虫阶段中的转录。与公共卫生有关：近10％的美国人生活在球虫病的特有地区，而感染者中约有5％发展出危及生命的疾病。有症状的感染赋予长期免疫力，因此可以进行疫苗接种。同样，当致病性基因被禁用时，毒力会降低，这表明这些基因产物的药物靶向应有效。