Molecular Phenotypes for Lung Diseases

描述（由申请人提供）：我们实验室的长期目标是了解炎症性肺部疾病的免疫病理学基础。本研究旨在了解microRNA （miRNA）和piwi相互作用蛋白RNA（转座子沉默RNA； piRNA）在以慢性阻塞性肺疾病（chronic obstructive pulmonary disease， COPD）和肺实质损失（肺气肿）为特征的吸烟相关肺部疾病中的意义。烟草烟雾引起的慢性阻塞性肺病/肺气肿目前是工业化世界第四大死因，预计不久将成为第三大死因。尽管戒烟，所有吸烟者中的一部分最终发展为COPD/肺气肿，这表明慢性炎症是疾病的基础，在很大程度上是由遗传因素决定的。由于慢性阻塞性肺病/肺气肿通常在晚期诊断，此时不可逆的肺破坏已导致肺功能和生活质量显著受损，因此需要在慢性阻塞性肺病/肺气肿病程早期出现的严重肺病标志物，并可用于预测肺功能的快速丧失。我们之前已经证明肺气肿与自身免疫CD4+ T细胞和B细胞对肺主要结构基质蛋白弹性蛋白的反应有关。此外，T辅助型1 （Th1）细胞诱导的趋化因子，包括CXCL10，协调基质金属蛋白酶（MMPs）的上调，最终导致弹性蛋白破坏和肺结构完整性的丧失。因此，吸烟者的T细胞和B细胞特异性抗弹性蛋白反应是晚期肺破坏的潜在有价值的指标，但尚不清楚这些炎症标志物是否在无症状吸烟者中发展得足够早，以提供临床有用的预测。mirna是21nt RNA转录物，结合mrna的3'非翻译区（UTR）抑制蛋白质翻译。在白血病、前列腺癌、牛皮癣等慢性炎症疾病中，大约460种已知的人类mirna的独特表达模式先前已被证明与临床显著结果相关。我们假设肺mirna和密切相关的pirna的独特表达模式与抗弹性蛋白自身免疫的炎症标志物相关。此外，我们假设肺气肿的肺miRNA标记物在同一个体的外周血中重现，并可用于预测自身免疫功能障碍的发生。为了验证这些假设，我们将在人肺和外周血单核细胞短转录组中建立主要的miRNA和piRNA特征，这些特征表征吸烟诱导的COPD/肺气肿；确定控制人类吸烟诱导的COPD/肺气肿的miRNA依赖调控途径；并确定人类Th1和Th17细胞特征的miRNA和piRNA关系。（摘要结束）

DESCRIPTION (provided by applicant): The long-term objective of our laboratories is to understand the immunopathologic basis of inflammatory lung diseases. This proposal specifically seeks to understand the significance of microRNA (miRNA) and piwi interacting protein RNA (transposon silencing RNA; piRNA) signatures in smoking-related lung disease marked by chronic obstructruction (chronic obstructive pulmonary disease; COPD) and lung parenchymal loss (emphysema). Tobacco smoke induced COPD/emphysema is now the fourth leading cause of death in the industrialized world and is expected shortly to become the third. Despite smoke cessation, a subset of all smokers ultimately develop COPD/emphysema, suggesting that the chronic inflammation that underlies disease is, to a large degree determined by genetic factors. Because COPD/emphysema is often diagnosed at a late stage, when irreversible lung destruction has resulted in significantly impaired lung function and quality of life, markers of severe lung disease that appear early in the course of COPD/emphysema and which can be used to predict rapid loss of lung function are needed. We have previously demonstrated that emphysema is associated with autoimmune CD4+ T cell and B cell responses directed against the major structural matrix protein of the lung, elastin. Moreover, T helper type 1 (Th1) cell-elicited chemokines, including CXCL10, coordinate the upregulation of matrix metalloproteinases (MMPs) that ultimately lead to elastin destruction and the loss of lung structural integrity. Thus, T cell, but also B cell, specific anti-elastin responses in smokers are potentially valuable indicators of later lung destruction, but it remains unclear if these inflammatory markers develop sufficiently early in asymptomatic smokers to provide clinically useful predictions. MiRNAs are 21nt RNA transcripts that bind to the 3' untranslated region (UTR) of mRNAs to suppress protein translation. Unique expression patterns of the approximately 460 known human miRNAs in diseases as diverse as leukemia, prostate cancer, the chronic inflammatory conditions such as psoriasis, have previously been shown to correlate with clinically significant outcomes. We hypothesize that unique expression patterns of lung miRNAs and closely related piRNAs correlate with inflammatory markers of anti-elastin autoimmunity. Moreover, we postulate that lung miRNA markers of emphysema are recapitulated in peripheral blood of the same individuals and may be used to predict the onset of autoimmune dysfunction. To test these hypotheses, we will establish primary miRNA and piRNA signatures within the human lung and peripheral blood mononuclear cell short transcriptomes that characterize smoking-induced COPD/emphysema; identify miRNA dependent regulatory pathways controlling human smoking-induced COPD/emphysema; and determine the miRNA and piRNA relationships that characterize human Th1 and Th17 cells. (End of Abstract)