Molecular Genetics of Pathogen Recognition Receptors in COPD

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）是一个重大的公共卫生问题。到2020年，这种使人衰弱的疾病预计将成为世界上第三大最常见的死亡原因和第五大最常见的残疾原因。职业性粉尘暴露是COPD的重要危险因素，多达15%的COPD病例可归因于职业暴露。农业是与COPD相关的职业之一，农民中COPD的患病率为17- 32%，即使调整了性别，年龄和吸烟等竞争风险。虽然在各种农业工作环境中的多种成分可能参与COPD的发展，但细菌和真菌成分已成为农业工作环境中的主要关注因素。细菌、真菌和它们各自的组分通过先天免疫系统经由病原体识别受体被识别和发出信号，所述病原体识别受体包括Toll样受体、Dectin-1簇受体和NOD样受体。我们在这个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，并有助于疾病的易感性。这些受体及其辅助分子的单核苷酸多态性已被确定;然而，还没有流行病学研究检查这些病原体识别受体在COPD中的作用。本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组分相互作用的辅助分子的遗传变异改变了农业暴露人群对COPD的易感性。此外，我们假设这些基因的功能多态性可以通过受体表达或配体-受体刺激来识别。我们将通过以下具体目标来解决这些假设：在农业暴露受试者中进行的病例对照研究中，确定结合革兰氏（+）和革兰氏（-）细菌组分以及真菌组分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/或肺功能相关;并确定这些多态性是否与受体表达和血液单核细胞对它们各自配体刺激的反应有关。对影响农业暴露退伍军人COPD的基因组学和潜在新途径的评估研究不足，这是一个高度创新的假设，可能会导致我们对普通人群COPD的整体理解的进步。我们预计，该项目可以推动我们开发基于药物遗传学的COPD治疗方法，并解决VA对基因组医学的倡议。) ) 公共卫生相关性： 项目叙述农业对弗吉尼亚州中西部卫生保健网络（VISN 23）的经济至关重要，农村退伍军人是农业劳动力的一部分。慢性阻塞性肺病是困扰退伍军人的常见疾病。虽然吸烟显然是COPD的一个危险因素，但农业工作尤其与COPD有关。对影响农业暴露退伍军人COPD的基因组学和潜在的新信号通路的评估研究不足，这是一个创新的假设，可能会导致我们对普通人群COPD的整体理解的进步。这项工作是第一次检查病原体识别受体基因与暴露于农业的个体中COPD的复杂关联，考虑到COPD与残疾，治疗费用不断上升和农民死亡率升高的关联，这一点很重要。我们预计，该项目将有助于更具体的预防和治疗策略，并解决VA对基因组医学的倡议。)

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. ) ) PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Agriculture is vital to the economy of the VA Midwest Health Care Network (VISN 23) and rural veterans are part of the workforce in agriculture. COPD is a frequent condition that afflicts veterans. Although cigarette smoking is clearly a risk factor for COPD, agricultural work in particular is associated with COPD. Assessment of the genomics and potential novel signaling pathways that influence COPD in veterans with agricultural exposure is understudied and an innovative hypothesis which could lead to advances in our overall understanding of COPD in the general population. This effort is the first to examine the complex association of pathogen recognition receptor genes and COPD in individuals exposed to agriculture, important given the association of COPD with disability, escalating treatment costs and heightened mortality among farmers. We anticipate that this project will contribute to more specific prevention and therapeutic strategies and address the VA initiative towards genomic medicine. )