Role of unique ADP-ribosylating vacuolating Mycoplasma pneumoniae toxin i

独特的 ADP-核糖基化空泡肺炎支原体毒素 i 的作用

• 批准号: 8705990
• 负责人: JOEL Barry BASEMAN
• 金额: $ 255.36万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705990
• 关键词: Acute; Address; Adult; Allergic; Allergic Disease; Antibodies; Asthma; Autopsy; Basic Science; Binding; Biological Assay; Biology; Biopsy; Cells; Child; Chronic; Clinical; Clinical Investigator; Clinical Research; Collaborations; Commit; Community Acquired Respiratory Distress Syndrome Toxin; Development; Diagnostic; Disease; Doctor of Philosophy; Essential Amino Acids; Evaluation; Fab Immunoglobulins; Fertilization; Functional disorder; Goals; Health; Human; Inflammation; Injury; Lead; Link; Lung; Lung diseases; Mediating; Mediator of activation protein; Modeling; Mus; Mycoplasma pneumoniae; Pathologic; Pathology; Patients; Pneumonia; Postdoctoral Fellow; Prevention; Procedures; Process; Proteins; Pulmonary Surfactant-Associated Protein A; Qualitative Evaluations; Reagent; Research; Research Project Grants; Resources; Role; Sampling; Structure; Testing; Time; Toxin; Virulence; Virulence Factors; X ray diffraction analysis; X-Ray Diffraction; airway inflammation; biophysical techniques; clinical material; cofactor; follow-up; graduate student; injured airway; innovation; neutralizing monoclonal antibodies; novel diagnostics; novel therapeutics; rapid detection; success; therapeutic vaccine; three dimensional structure

DESCRIPTION (provided by applicant): The San Antonio Asthma and Allergic Diseases Cooperative Research Center (SA-AADCRC) represents a tightly focused, integrative and innovative effort to understand the role of Mycoplasma pneumoniae and its unique ADP-ribosylating and vacuolating toxin, designated Community Acquired Respiratory Distress Syndrome ToXin (CARDS TX) as important mediators of acute and chronic airway diseases, including new onset asthma and exacerbations, as well as persistent pulmonary dysfunction in children and adults. The basic science and clinical investigators who comprise the SA-AADCRC team share broad expertise and are highly collaborative. The SA-AADCRC's broad strategy of attack interlinks basic science and clinical research projects and cores. Project 1 uses the murine model and human materials to address fundamental questions on how CARDS TX induces asthma-like disease and exacerbates allergic pulmonary inflammation. Project 2 focuses on identifying CARDS TX ADP-ribosylating airway protein targets, delineating functionally important CARDS TX domains and essential amino acids that mediate CARDS TX binding to human surfactant protein A (SP-A) and airway cells, and generating antibody reagents that block/neutralize CARDS TX. Project 3 applies state-of-the-art biophysical techniques to uncover the structure and action of CARDS TX by using single crystal X-ray diffraction to determine CARDS TX three dimensional structure in the presence and absence of its cofactor NAD; neutralizing monoclonal antibody Fab fragments; and surfactant protein-A (SP-A). Clinical Core will collect human material from subjects with well controlled asthma, poorly controlled asthma and healthy controls and help in evaluation and follow-up of patient-related studies. Diagnostic Core will process clinical and experimental samples for diagnostic analysis by providing highly sensitive and specific diagnostic assays for rapid detection of M. pneumoniae CARDS TX. Pathology Core will provide necessary biopsy and necropsy procedures, lung pathology interpretation, histochemical and immunocytochemical evaluations, and qualitative and semiquantitative histopathologicai analyses. Administrative Core will oversee all SA-AADCRC-related activities and coordinate interactions and collaborations between projects and cores. Therefore, the SA-AADCRC represents a network of collaborators/colleagues who continuously ask fundamental and translational questions about asthma, airway-related pathologies, immunopathogenesis, and M. pneumoniae/CARDS TX biology and virulence mechanisms.

描述(由申请人提供)：圣安东尼奥哮喘和变态反应性疾病合作研究中心(SA-AADCRC)代表着一项专注、整合和创新的努力，旨在了解肺炎支原体及其独特的ADP核糖化和空泡化毒素(命名为社区获得性呼吸窘迫综合征毒素(CADS TX))作为急性和慢性呼吸道疾病(包括新发哮喘和加重)以及儿童和成人持续性肺功能障碍的重要介质所起的作用。组成SA-AADCRC团队的基础科学和临床研究人员共享广泛的专业知识，并高度合作。SA-AADCRC的广泛攻击性战略将基础科学和临床研究项目和核心联系在一起。项目1使用小鼠模型和人类材料来解决CARDS TX如何诱导哮喘样疾病和加剧过敏性肺部炎症的基本问题。项目2的重点是识别CARDS TX-ADP-使呼吸道蛋白靶标核糖化，描绘功能上重要的CARDS TX结构域和调节CARDS TX与人表面活性蛋白A(SP-A)和呼吸道细胞结合的必需氨基酸，以及产生阻断/中和CARDS TX的抗体试剂。项目3应用最先进的生物物理技术来揭示CARDS TX的结构和作用，方法是在存在和不存在辅因子NAD的情况下，使用单晶X射线衍射法确定CADS TX的三维结构；中和单抗Fab片段；以及表面活性蛋白-A(SP-A)。临床核心公司将从哮喘控制良好、哮喘控制不佳和健康对照的受试者那里收集人体材料，并帮助评估和跟踪与患者相关的研究。诊断核心公司将为诊断分析处理临床和实验样本，为快速检测肺炎支原体卡片Tx提供高度敏感和特异的诊断分析方法。病理核心将提供必要的活检和尸检程序、肺病理解释、组织化学和免疫细胞化学评估，以及定性和半定量的组织病理学分析。管理核心将监督所有与SA-AADCRC相关的活动，并协调项目和核心之间的互动和合作。因此，SA-AADCRC代表了一个合作者/同事网络，他们不断提出关于哮喘、与呼吸道相关的病理学、免疫发病机制以及肺炎支原体/卡介苗TX生物学和毒力机制的基本和翻译问题。