Role of CARDS Toxin in M. pneumoniae Associated Asthma in Mice

卡毒素在小鼠肺炎支原体相关哮喘中的作用

• 批准号: 7686472
• 负责人: PETER H DUBE
• 金额: $ 21.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686472
• 关键词: Accounting; Acute; American; Animal Model; Animals; Asthma; Bacterial Infections; Biochemical; Biological Assay; Cells; Chronic; Chronic Disease; Clinical; Collaborations; Community Acquired Respiratory Distress Syndrome Toxin; Complex; Complex Mixtures; Confusion; Control Animal; Development; Diagnostic; Disease; Economics; Ensure; Environmental Risk Factor; Etiology; Experimental Designs; Experimental Models; Exposure to; Extrinsic asthma; Gene Expression; Genes; Genetic; Goals; Histopathology; Human; Immune; Immune response; Immune system; Immunophenotyping; Inbred BALB C Mice; Individual; Infection; Intoxication; Length; Link; Lung; Lung diseases; Mediating; Methodology; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Mycoplasma pneumoniae; Numbers; Ovalbumin; Pathogenesis; Pathology; Phenotype; Physiological; Play; Pneumonia; Population; Prevalence; Protocols documentation; Quality of life; Reagent; Relative (related person); Research Personnel; Respiratory Tract Infections; Rodent; Rodent Model; Role; Sampling; Scientist; Specimen; Stimulus; Symptoms; Testing; Therapeutic Intervention; Toxin; Virulence; Virulence Factors; Work; abstracting; airway hyperresponsiveness; airway remodeling; cytokine; in vivo; insight; mortality; mouse model; mutant; novel; null mutation; research study; response

Asthma is a complex disease that afflicts over 15 million Americans. Despite the apparent increase in prevalence of disease within our population, asthma is still a poorly understood disease. This is in part due to the complex mixture of genetic factors, environmental stimuli, and immune system status that impacts disease development and progression. One under appreciated and controversial factor in the etiology of asthma is the role that atypical bacterial infections, such as those caused by Mycoplasma pneumoniae, play in initiating, exacerbating and prolonging airway-related symptoms and pathologies. A major part of the confusion is the lack of reliable and relevant diagnostic methodologies and bona fide virulence determinants that directly link M. pneumoniae to asthma pathogenesis. Recently a unique M. pneumoniae toxin (CARDS TX: Community Acquired Respiratory Distress Syndrome Toxin) was discovered (see Preliminary results section and Project 4) that replicates the cytokine responses, pathology, and changes in airway hyperresponsiveness observed with M. pneumoniae respiratory infections and M. pneumoniae-assoc\ated asthma. We consider this finding a potential major breakthrough and hypothesize that CARDS TX may be responsible for acute, chronic, and exacerbation of asthma. To test this hypothesis, we will take advantage of the BALB/c-ovalbumin model of allergic asthma to test the following Specific aims: 1) Determine the contribution of our newly discovered ADP ribosylating, vacuolating CARDS TX to the pathogenesis of M. pneumoniae associated allergic asthma using established murine models, 2) Investigate the role of CARDS TX in the pathogenesis of asthma associated with M. pneumoniae infection. Mice will be infected with wild type M. pneumoniae or M. pneumoniae with a null mutation in the CARDS TX gene. Pathogenesis will be evaluated in the BALB/c mouse model with and without ovalbumin-induced airway hyper-responsiveness, to elucidate the role of CARDS TX in the context of the infectious model, and 3) Investigate the activity of CARDS TX in vivo. We will refine our analysis of the impact of CARDS TX on M. pneumon/ae-mediated respiratory disease through the analysis of CARDS TX-induced gene expression, localization/co-localization, and biochemical activity in vivo using the BALB/c mouse model with and without ovalbumin-induced airway hyper-responsiveness. The studies outlined in this project provide an asthma experimental model to correlate with clinical findings from Project 3; experiments using chronic models of infection described in Project 1; mutants, reagents and biochemical and molecular observations developed in Project 4; and Pathology Core B expertise.

哮喘是一种复杂的疾病，困扰着超过1500万美国人。尽管明显增加， 尽管哮喘在我国人口中的患病率很高，但哮喘仍然是一种知之甚少的疾病。这部分是由于 遗传因素、环境刺激和免疫系统状态的复杂混合物， 疾病的发展和进展。一个未被重视和有争议的因素在病因学 哮喘是由非典型细菌感染，如肺炎支原体引起的， 引发、加重和延长气道相关症状和病理。的主要部分 困惑是缺乏可靠和相关的诊断方法和真正的毒力决定因素 直接连接M。肺炎对哮喘发病机制的影响。最近，一个独特的M。肺炎毒素 TX：社区获得性呼吸窘迫综合征毒素）被发现（见初步结果 部分和项目4），其复制了细胞因子反应、病理学和气道高反应性的变化 观察M。pneumoniae呼吸道感染和M.肺炎性肺炎 哮喘我们认为这一发现是一个潜在的重大突破，并假设， 负责急性、慢性和哮喘恶化。为了验证这一假设，我们将利用 本研究旨在建立BALB/c-卵清蛋白致敏性哮喘模型，具体目的如下：1）测定哮喘小鼠血清中 我们新发现的ADP核糖基化、空泡化的β-TX在M. 使用已建立的小鼠模型研究肺炎相关的过敏性哮喘，2）研究肺炎相关的过敏性哮喘的作用。 TX在哮喘发病中的作用与M.肺炎感染。老鼠会感染野生的 M型。pneumoniae或M.肺炎，在CITTX基因中具有无效突变。发病机理将是 在有和没有卵清蛋白诱导的气道高反应性的BALB/c小鼠模型中评价， 在感染模型的背景下，阐明CITTX的作用，和3）研究CITTX的活性。 在体内的TXB 2。我们将完善我们的分析，对M。肺炎/AE介导 通过分析MTX诱导的基因表达，定位/共定位， 使用有和没有卵清蛋白诱导的气道的BALB/c小鼠模型， 反应过度本项目概述的研究提供了一种哮喘实验模型， 与项目3的临床发现相关;使用中描述的慢性感染模型的实验 项目1;项目4开发的突变体、试剂以及生物化学和分子观测;以及 病理学核心B专业知识。