CANDIDA GENE EXPRESSION DURING OROPHARYNGEAL INFECTION

口咽感染期间念珠菌基因表达

• 批准号: 8633034
• 负责人: AARON P MITCHELL
• 金额: $ 17.99万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633034
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Aspartic Endopeptidases; Bacterial Adhesins; Basic Science; Biological Assay; Candida; Candida albicans; Candidate Disease Gene; Candidiasis; Cell Line; Cell Surface Proteins; Cell surface; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Communities; Data; Data Set; Diabetes Mellitus; Disease; Drug resistance; Eating; Environment; Epithelial Cells; Epithelium; Fluconazole; Future; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genome; Goals; HIV; Head and Neck Cancer; Histopathology; Human; In Vitro; Individual; Infection; Intravenous; Investments; Measurement; Modeling; Molecular Profiling; Mus; Oral; Oral candidiasis; Oropharyngeal; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Prevalence; Process; Proteins; RNA; Regulator Genes; Relapse; Research Personnel; Risk; Sampling; Signal Pathway; Stress; Surface; System; Technology; Testing; Tissues; Tongue; Transcription factor genes; Validation; chromatin immunoprecipitation; design; drug development; follow-up; fungus; in vivo; mutant; nano-string; new technology; novel; oropharyngeal thrush; pathogen; prospective; public health relevance; reconstitution; research study; response; statistics; therapeutic development; therapeutic target; therapeutic vaccine; transcription factor

DESCRIPTION (provided by applicant): Oropharyngeal candidiasis (OPC) is among the first clinical manifestations of AIDS. It occurs in 50-95% of HIV+ individuals during the progression to AIDS, and overall prevalence among AIDS patients is estimated by the CDC at 9-31%. This infection is caused primarily by Candida albicans, a commensal fungus that can cause mucosal and invasive infections. Our overall objective is to understand the C. albicans gene products that govern host interaction and contribute to pathogenesis of OPC. We will use a new gene expression assay technology, nanoString nCounter RNA measurements, to determine levels of C. albicans gene expression during infection in widely used a murine OPC model. Our preliminary results correlate well with prior patient sample and in vitro infection gene expression data, but also reveal extensive stress-responsive gene expression and rewiring of transcription factor-target gene relationships. Proposed studies focus on two classes of gene products: transcription factors, and surface and secreted proteins. We have chosen transcription factor genes because they are a highly regulated gene set, and their products have been or can be connected to functions through systematic mutant screens, expression profiling, and chromatin immunoprecipitation. We have chosen surface and secreted protein genes because their products are engaged in direct interaction with host cells, and because they present the most accessible therapeutic targets. We will develop a reference dataset that explores expression of these genes, and extend the analysis with functional validation. Our findings will generate new hypotheses and inform choices of genes and pathways that can be pursued by all investigators in the community. Statement of Public Health Relevance: Our studies focus on oropharyngeal candidiasis, an infection for which AIDS patients are at risk. Our approach will identify high-priority therapeutic targets expressed by the pathogen that causes this infection. The results will guide drug development and will help to focus basic research studies on gene products that are directly relevant to this disease.

描述（由申请人提供）：口咽念珠菌病（OPC）是艾滋病最早的临床表现之一。它发生在50-95%的HIV+个体进展为AIDS期间，CDC估计AIDS患者的总体患病率为9- 31%。这种感染主要是由白色念珠菌引起的，白色念珠菌是一种可引起粘膜和侵袭性感染的真菌。我们的总体目标是了解C。白念珠菌的基因产物控制宿主相互作用，并有助于OPC的发病机制。我们将使用一种新的基因表达检测技术，nanoString nCounter RNA测量，以确定C水平。在广泛使用的小鼠OPC模型中，我们的初步结果与先前的患者样本和体外感染基因表达相关 数据，而且还揭示了广泛的应激反应基因表达和转录因子-靶基因关系的重新连接。拟议的研究集中在两类基因产物：转录因子，表面和分泌蛋白。我们之所以选择转录因子基因，是因为它们是一个高度调控的基因组，并且它们的产物已经或可以通过系统的突变体筛选、表达谱分析和染色质免疫沉淀与功能相关联。我们选择了表面和分泌蛋白基因，因为它们的产物与宿主细胞直接相互作用，而且它们是最容易获得的治疗靶点。我们将开发一个参考数据集，探索这些基因的表达，并通过功能验证扩展分析。我们的发现将产生新的假设，并为社区中所有研究人员可以追求的基因和途径的选择提供信息。公共卫生相关性声明：我们的研究重点是口咽念珠菌病，这是一种艾滋病患者面临的感染风险。我们的方法将确定引起这种感染的病原体表达的高优先级治疗靶点。结果将 指导药物开发，并将有助于将基础研究的重点放在与这种疾病直接相关的基因产物上。