The Role of Nod1 and Nod2 in the Pathogeneisis of Legionella Pneumophila Pneumoni

Nod1和Nod2在嗜肺军团菌发病机制中的作用

• 批准号: 7879955
• 负责人: William Richard Berrington
• 金额: $ 13.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879955
• 关键词: Aerosols; Animals; Antigens; Binding; Clinical; Commit; Communicable Diseases; Communities; Detection; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Exposure to; Family; Future; Genetic Predisposition to Disease; Grant; Host Defense; Human; Human Genetics; Immune; Immune response; Immunosuppressive Agents; Immunotherapeutic agent; In Vitro; Individual; Intervention; Knockout Mice; Knowledge; Lead; Legionella; Legionella pneumophila; Lung; Lung diseases; Mastigophora; Mentors; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Nucleotides; Organism; Outcome; Pathogen detection; Patients; Pattern; Phagolysosome; Pharmaceutical Preparations; Pneumonia; Population; Public Health; Research; Research Personnel; Resources; Risk Factors; Role; Severity of illness; Smoker; Toll-like receptors; Training; Training Programs; Universities; Washington; Water Supply; cohort; design; detector; experience; improved; in vivo; leucine-rich repeat protein; macrophage; microbial; mortality; pathogen; receptor; respiratory; response; retinal rods; vaccination strategy; Aerosols; Animals; Antigens; Binding; Clinical; Commit; Communicable Diseases; Communities; Detection; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Exposure to; Family; Future; Genetic Predisposition to Disease; Grant; Host Defense; Human; Human Genetics; Immune; Immune response; Immunosuppressive Agents; Immunotherapeutic agent; In Vitro; Individual; Intervention; Knockout Mice; Knowledge; Lead; Legionella; Legionella pneumophila; Lung; Lung diseases; Mastigophora; Mentors; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Nucleotides; Organism; Outcome; Pathogen detection; Patients; Pattern; Phagolysosome; Pharmaceutical Preparations; Pneumonia; Population; Public Health; Research; Research Personnel; Resources; Risk Factors; Role; Severity of illness; Smoker; Toll-like receptors; Training; Training Programs; Universities; Washington; Water Supply; cohort; design; detector; experience; improved; in vivo; leucine-rich repeat protein; macrophage; microbial; mortality; pathogen; receptor; respiratory; response; retinal rods; vaccination strategy

DESCRIPTION (provided by applicant): The PI of this grant is an M.D., Ph.D. who is committed to academic research and recently completed his clinical training in the Division of Infectious Disease at the University of Washington in Seattle. The proposal describes a 5 year training program designed to establish the PI as an independent researcher in the field of innate immunity in the host protection to respiratory pathogens. Specifically, the proposal is focused on the role of intracellular Nucleotide Oligermerization Domain (NOD)-like receptors, Nodi and Nod2, in the detection of and protection from Legionella pneumophila (Lp) pneumonia, an important cause of community acquired pneumonia. In our preliminary studies we have shown that Lp is able to detect Lp, and that mice deficient in Nodi and Nod2 have altered immune responses to Lp. In order to determine the relevance of Nodi and Nod2 in the innate host immune response to Lp, Aim 1 proposes to determine the mechanisms by which Nodi and Nod2 deficiency lead to impaired inmiune responses in the whole animal. In Aim 2, we willdetermine the cellular mechanism of the Nodi and Nod2 response to Lp. Lastly, in Aim 3 we plan to define human significance by analyzing human genetic variability in Nodi and Nod2 and identify association to Lp pneumonia in a cohort of patients acquired Lp pneumonia following exposure to the pathogen. Completion of these aims will allow for better unstanding of the role of intracellular pathogen detection in pulmonary pneumonias possibly leading to development of immunotherapeutic interventions to individuals with known disease or improved vaccination strategies. The resources and expertise made available to the PI is uniquely suited for the project. Dr Thomas Hawn, the primary mentor, is an expert in the fields of innate immunity and human genetics. Dr. Shawn Skerrett has extensive experience with mouse knockout models of Lp pneumonia. The combination is uniquely suited to understanding innate immune responses to respiratory pathogens. This proposal seeks to improve public health by increasing our knowledge of the host immune response to pulmonary pathogens to one day help design beneficial interventions to improve outcome. RELEVANCE: Legionella pneumophila is an important lung pathogen, known to cause pneumonia in a significant proportion of the population. This proposal seeks to identify the mechanism of the host repsonse to this Legionella. Understanding the host immune resposne to Lp may lead to improved patient management of active Lp pneumonia, or to improved vaccination strategies in the future.

描述（由申请人提供）：本赠款的PI是医学博士学位。他致力于学术研究，并最近在西雅图华盛顿大学完成了他在传染病的临床培训。该提案描述了一项为期5年的培训计划，旨在将PI建立为宿主对呼吸道病原体保护的先天免疫领域的独立研究人员。具体而言，该提案的重点是细胞内核苷酸寡聚结构域（NOD）样受体NODI和NOD2在检测和保护肺炎军团肺炎（LP）肺炎的保护中，这是社区获得肺炎的重要原因。在我们的初步研究中，我们表明LP能够检测LP，并且缺乏NODI和NOD2的小鼠对LP的免疫反应改变了。为了确定NODI和NOD2在先天宿主对LP的免疫反应中的相关性，AIM 1提出了确定NODI和NODI和NOD2缺乏导致整个动物中的含量反应受损的机制。在AIM 2中，我们将确定NODI的细胞机制和NOD2对LP的反应。最后，在AIM 3中，我们计划通过分析NODI和NOD2的人类遗传变异性来定义人类的意义，并确定在暴露于病原体后获得LP肺炎的患者中与LP肺炎的关联。这些目的的完成将使细胞内病原体检测在肺炎中的作用更好，这可能会导致对患有已知疾病或改善疫苗接种策略患者的免疫治疗干预措施的发展。 PI提供的资源和专业知识非常适合该项目。主要导师托马斯·霍恩（Thomas Hawn）博士是先天免疫和人类遗传学领域的专家。肖恩·斯科雷特（Shawn Skerrett）博士在LP肺炎的小鼠基因敲除模型方面具有丰富的经验。该组合非常适合理解对呼吸道病原体的先天免疫反应。该建议旨在通过提高我们对宿主对肺病原体的免疫反应的了解来改善公共卫生，这有助于设计有益的干预措施以改善预后。 相关性：肺炎军团菌是一种重要的肺病原体，已知会在很大一部分人群中引起肺炎。该提议旨在确定宿主对这个军团菌的机制。了解宿主对LP的免疫呼吸可能会改善活性LP肺炎的患者管理，或者将来改善疫苗接种策略。