Molecular Genetics of Pathogen Recognition Receptors in COPD

描述(由申请人提供)： 摘要慢性阻塞性肺疾病(COPD)是一大公共卫生问题。到2020年，这种使人衰弱的疾病预计将成为世界上第三大常见死亡原因和第五大最常见的残疾原因。职业性接触粉尘是慢性阻塞性肺疾病的一个重要风险因素，多达15%的COPD病例可能与职业性接触有关。农业是与慢性阻塞性肺病相关的职业之一，即使在对性别、年龄和吸烟等相互竞争的风险进行调整后，农民中的慢阻肺患病率也被发现为17%-32%。尽管各种农业工作环境中的多种成分可能参与了慢性阻塞性肺疾病的发展，但细菌和真菌成分已经成为农业工作环境中令人担忧的主要因素。细菌、真菌和它们各自的成分通过病原体识别受体识别并通过天然免疫系统传递信号。病原体识别受体包括Toll样受体、Dectin-1簇受体和NOD样受体。我们在这项建议中的方法的前提是，随着不同的环境暴露，不同的基因可能被激活，并有助于疾病易感性。这些受体及其附属分子中的单核苷酸多态性已经被发现；然而，还没有流行病学研究来检验这些病原体识别受体在COPD中的作用。这项研究的总体工作假设是，病原体识别受体及其与细菌和真菌成分相互作用的辅助分子的遗传变异改变了农业接触人群中COPD的易感性。此外，我们假设这些基因的功能多态可以通过受体表达或配体-受体刺激来识别。我们将以以下具体目标解决这些假设：在一项在农业接触者中进行的病例对照研究中，确定与革兰氏(+)和革兰氏(-)细菌成分以及真菌成分结合的病原体识别受体的遗传变异是否与COPD、慢性支气管炎症状和/或肺功能有关；并确定这些多态与血液单个核细胞对各自配体刺激的受体表达和反应是否存在关联。对影响有农业接触的退伍军人COPD的基因组学和潜在的新途径的评估未得到充分研究，并提出了一个高度创新的假说，可能导致我们在普通人群中对COPD的总体理解取得进展。我们期望这个项目可以推动我们朝着基于药物遗传学的COPD治疗方法的发展，并解决VA向基因组医学的倡议。))

DESCRIPTION (provided by applicant): ABSTRACT Chronic obstructive pulmonary disease (COPD) is a major public health problem. This debilitating condition is projected to be the third most common cause of death and the fifth most common cause of disability in the world by 2020. Occupational exposure to dusts is a significant risk factor for COPD and as much as 15% of COPD cases may be attributable to occupational exposures. Farming is among the occupations associated with COPD and the prevalence of COPD among farmers has been found to be 17- 32%, even after adjustment for competing risks such as gender, age and smoking. Although it is likely that multiple components in various agricultural work environments are involved in the development of COPD, bacterial and fungal components have emerged as major factors of concern in agricultural work settings. Bacteria, fungi and their respective components are recognized and signal through the innate immune system via pathogen recognition receptors, which include the Toll-Like Receptors, the Dectin-1 cluster receptors and the NOD-Like receptors. The premise of our approach in this proposal is that with different environmental exposures, different genes may be activated and contribute to disease susceptibility. Single nucleotide polymorphisms in these receptors and their accessory molecules have been identified; however there have been no epidemiological studies examining the role of these pathogen recognition receptors in COPD. The overall working hypothesis of this study is that genetic variation in pathogen recognition receptors and their accessory molecules that interact with bacterial and fungal components alters susceptibility to COPD in an agriculturally exposed population. Furthermore, we hypothesize that functional polymorphisms in these genes can be recognized by receptor expression or ligand- receptor stimulation. We will address these hypotheses with the following specific aims: In a case-control study among agriculturally-exposed subjects, determine whether genetic variation in pathogen recognition receptors that bind Gram (+) and Gram (-) bacterial components, as well as fungal components, are associated with COPD, chronic bronchitis symptoms and/or lung function; and to determine whether there is an association of these polymorphisms with receptor expression and responses of blood mononuclear cells to stimulation with their respective ligands. Assessment of the genomics and potential novel pathways that influence COPD in veterans with agricultural exposure is understudied and a highly innovative hypothesis which could lead to advances in our overall understanding of COPD in the general population. We anticipate that this project could advance us towards the development of pharmacogenetic-based treatments for COPD and address the VA initiative towards genomic medicine. ) )