Host Defenses and Susceptibility to Tuberculosis

宿主防御和结核病易感性

• 批准号: 7036086
• 负责人: Gerard J Nau
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036086
• 关键词: Macaca; Primates; animal tissue; gene expression; gene expression profiling; genes; human; infection; lung; model; tissues; tuberculosis

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis remains a global public health problem. The natural history of tuberculosis (TB) can vary widely among individuals; while most patients have sub-clinical, latent infection, a subpopulation of individuals infected with M. tuberculosis progress to primary disease or reactivation TB. A rigorous comparison of susceptible and resistant individuals would be useful to study mechanisms of pathogenesis, but controlled infections of humans is not possible. The goal of this exploratory (R21) proposal is to establish the basic framework needed to identify host defense genes associated with different TB disease states by gene expression profiling. We will exploit a non-human primate (NHP) model of TB as a system to evaluate host defenses. Using high density DNA microarrays, we will measure gene expression in lung tissue of normal macaques and of infected macaques that exhibit two distinct disease states: active disease and latent infection. We hypothesize differential patterns of gene expression will be responsible for pathologic manifestations (granuloma versus non-granulomatous infection) and clinical conditions (active versus latent). This information will increase our understanding of host defenses and pathogenesis of M. tuberculosis. Our specific aims include: Aim 1: To determine the regional variability among grossly comparable lung tissue from the same animal, thereby evaluating the homogeneity of gene expression profiles. This will provide critical information on sampling bias and what is necessary to characterize an individual's response. Aim 2: To resolve some complexity of gene expression measured in M. tuberculosis-infected animals using known expression profiles. This will test the contributions of specific cell types and signaling pathways to the overall gene expression profile. Aim 3: To identify patterns of gene expression that distinguish between animals with active disease and latent infection. This will compare active and latent infection in an attempt to identify factors important in susceptibility to particular disease states. This work described in this application will establish a process to evaluate host defenses in the NHP model; a process that will be applicable to multiple future studies. Ultimately, representative genes will be evaluated for their role in immunity and host defenses, and as markers of vulnerability to clinical disease.

描述（由申请人提供）：结核分枝杆菌仍然是全球公共卫生问题。在个体中，结核病的自然历史（TB）可能差异很大。虽然大多数患者患有亚临床，潜在感染，但感染结核分枝杆菌的个体的亚群会发展为原发性疾病或重新激活TB。对易感和抗性个体的严格比较将有助于研究发病机理的机制，但无法控制人类的感染。该探索性（R21）提案的目的是建立通过基因表达分析确定与不同TB疾病状态相关的宿主防御基因所需的基本框架。我们将利用结核病的非人类灵长类动物（NHP）模型作为评估宿主防御的系统。使用高密度的DNA微阵列，我们将测量正常猕猴的肺组织中的基因表达，以及表现出两种不同疾病状态的感染猕猴的基因表达：活性疾病和潜在感染。我们假设基因表达的差异模式将负责病理表现（肉芽肿与非颗粒状感染）和临床状况（活动与潜在）。这些信息将增加我们对宿主防御和结核分枝杆菌发病机理的理解。我们的具体目的包括：目标1：确定来自同一动物的严重可比肺组织之间的区域变异性，从而评估基因表达谱的均匀性。这将提供有关采样偏差的关键信息，以及表征个人响应的必要信息。目的2：使用已知的表达谱在结核分枝杆菌感染动物中测得的基因表达的某些复杂性。这将测试特定细胞类型的贡献以及对整体基因表达谱的信号通路的贡献。目标3：确定区分活性疾病和潜在感染动物的基因表达模式。这将比较主动感染和潜在感染，以尝试确定对特定疾病状态敏感的重要因素。本应用程序中描述的这项工作将建立一个评估NHP模型中主机防御的过程；该过程将适用于以后的多个研究。最终，将评估代表性基因在免疫和宿主防御方面的作用，并作为临床疾病脆弱性的标志。