H. influenzae genes associated with COPD

与 COPD 相关的流感嗜血杆菌基因

• 批准号: 7069289
• 负责人: JANET R GILSDORF
• 金额: $ 37.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069289
• 关键词: bacteria infection mechanism; bacterial DNA; bacterial genetics; chronic obstructive pulmonary disease; clinical research; enzyme linked immunosorbent assay; genetic strain; host organism interaction; human subject; immunogenetics; immunomodulators; microarray technology; microorganism immunology; mucosal immunity; respiratory epithelium; respiratory infections; subtraction hybridization; virulence

DESCRIPTION (provided by applicant): PROJECT SUMMARY: Chronic obstructive pulmonary disease results from a complex interplay of environmental factors, host immune responses, and microbial factors. The bacterium Haemophilus influenzae colonizes the human respiratory tract and is an important pathogen associated with COPD. The overall goal of this study is to identify H. influenzae factors that contribute to the pathogenesis of COPD. The underlying principles exploited in this proposal are that H. influenzae are genetically highly variable and that natural selection preserves necessary genes among specific populations of bacteria. In Specific Aim 1 the prevalence of known H. influenzae virulence genes will be described among H. influenzae strains isolated from patients with COPD and from adults without COPD. In Specific Aim 2 additional genes that segregate differentially among H. influenzae isolated from patients with COPD and from adults without COPD will be identified. This gene discovery effort will utilize subtractive genomic hybridization to identify H. influenzae DNA fragments that correspond to genes present in a representative COPD H. influenzae strain but absent in a representative commensal strain. The prevalence of the resultant DNA fragments among COPD and non-COPD H. influenzae strains will be assessed using a bacterial genomic microarray technique. In addition, the corresponding genes of the COPD-associated DNA fragments will be defined and mapped on the H. influenzae chromosome, and the extent of the deletion in flanking regions of the commensal strain assessed. In Specific Aim 3, the co-occurrence of the potential COPD-associated virulence genes among COPD strains will be described and the relative contribution of each gene to the "COPD pathotype" will be determined using a classification tree analysis. In Specific Aim 4, the expression of immune mediators by human epithelial cells in response to H. influenzae of the "COPD pathotypes" will be measured using ELISA. PROJECT RELEVANCE: The results of this project will identify H. influenzae genes that are associated with COPD will describe their role in stimulating immune responses by human epithelial cells. These results will lead to a better understanding of the H. influenzae virulence pathways associated with COPD and lead to novel new strategies for prevention and management of COPD. (End of Abstract)

描述（由申请人提供）： 项目摘要：慢性阻塞性肺疾病是环境因素、宿主免疫反应和微生物因素复杂相互作用的结果。流感嗜血杆菌定植于人类呼吸道，是与慢性阻塞性肺病相关的重要病原体。本研究的总体目标是确定导致 COPD 发病机制的流感嗜血杆菌因素。该提案利用的基本原则是流感嗜血杆菌在遗传上具有高度可变性，并且自然选择保留了特定细菌种群中的必要基因。在具体目标 1 中，将描述从 COPD 患者和非 COPD 成人中分离的流感嗜血杆菌菌株中已知的流感嗜血杆菌毒力基因的流行情况。在具体目标 2 中，将鉴定从 COPD 患者和未患 COPD 的成人中分离出的流感嗜血杆菌之间存在差异分离的其他基因。这项基因发现工作将利用消减基因组杂交来鉴定流感嗜血杆菌 DNA 片段，这些片段对应于代表性 COPD 流感嗜血杆菌菌株中存在但在代表性共生菌株中不存在的基因。将使用细菌基因组微阵列技术评估 COPD 和非 COPD 流感嗜血杆菌菌株中所得 DNA 片段的流行率。此外，将定义 COPD 相关 DNA 片段的相应基因并将其映射到流感嗜血杆菌染色体上，并评估共生菌株侧翼区域的缺失程度。在具体目标 3 中，将描述 COPD 菌株中潜在的 COPD 相关毒力基因的共现，并使用分类树分析确定每个基因对“COPD 病理型”的相对贡献。在具体目标 4 中，将使用 ELISA 测量人类上皮细胞响应“COPD 病理型”流感嗜血杆菌的免疫介质表达。项目相关性：该项目的结果将鉴定与 COPD 相关的流感嗜血杆菌基因，并描述它们在刺激人类上皮细胞免疫反应中的作用。这些结果将有助于更好地了解与慢性阻塞性肺病相关的流感嗜血杆菌毒力途径，并产生预防和管理慢性阻塞性肺病的新策略。 （摘要完）