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: 8282892
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282892
• 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

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 (See inslructionsV 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.

这笔赠款的PI是医学博士学位。致力于学术研究并最近完成临床的人 西雅图华盛顿大学的传染病分区培训。该提议描述了5 年度培训计划旨在将PI建立为先天免疫领域的独立研究人员 宿主保护呼吸道病原体。 具体而言，该建议集中于细胞内核苷酸寡聚域（NOD）样的作用 受体，NODI和NOD2，在检测和免受肺炎军团菌（LP）肺炎的保护中 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能够检测到 LP，缺乏NODI和NOD2的小鼠对LP的免疫反应改变了。为了确定相关性 先天宿主对LP的免疫反应中的NODI和NOD2的AIM 1提议确定其机制 NODI和NOD2缺乏会导致整个动物的易变反应受损。在AIM 2中，我们将确定 NODI和NOD2对LP的响应的细胞机制。最后，在目标3中，我们计划通过 分析NODI和NOD2的人类遗传变异性，并确定与LP肺炎的关联 暴露于病原体后获得的LP肺炎。这些目标的完成将允许更好的不稳定 细胞内病原体检测在肺肺炎中的作用可能导致 对患有已知疾病或改善疫苗接种策略的个体的免疫治疗干预措施。 PI提供的资源和专业知识非常适合该项目。主要的托马斯·霍恩（Thomas Hawn）博士 导师是先天免疫和人类遗传学领域的专家。肖恩·斯科雷特（Shawn Skerrett）博士拥有丰富的经验 LP肺炎的小鼠敲除模型。该组合非常适合理解先天免疫 对呼吸道病原体的反应。该建议旨在通过提高我们对 宿主对肺病原体对一天的免疫反应有助于设计有益的干预措施以改善预后。 相关性（请参见Inslructionsv 肺炎军团菌是一种重要的肺病原体，已知会引起肺炎 人口比例。该提案旨在确定主机重新记录的机制 军团菌。了解宿主免疫呼吸对LP可能会改善患者的管理 活跃的LP肺炎，或改善未来的疫苗接种策略。

项目成果

Quantification of viral DNA and liver enzymes in plasma improves early diagnosis and management of herpes simplex virus hepatitis.

血浆中病毒 DNA 和肝酶的定量可改善单纯疱疹病毒肝炎的早期诊断和治疗。

• DOI: 10.1111/j.1365-2893.2010.01352.x
• 发表时间: 2011
• 期刊: Journal of viral hepatitis
• 影响因子: 2.5
• 作者: Beersma,MFC;Verjans,GMGM;Metselaar,HJ;Osterhaus,ADME;Berrington,WR;vanDoornum,GJ
• 通讯作者: vanDoornum,GJ