Molecular Phenotypes for Lung Diseases

描述(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基础。这项建议专门试图了解microRNA(MiRNA)和piwi相互作用蛋白RNA(转座子沉默RNA；piRNA)信号在以慢性阻塞性肺疾病(慢性阻塞性肺疾病；COPD)和肺实质丧失(肺气肿)为特征的吸烟相关肺部疾病中的意义。烟草烟雾导致的慢性阻塞性肺病/肺气肿现在是工业化世界的第四大死因，预计不久将成为第三大死因。尽管戒烟，但所有吸烟者中的一部分最终会患上COPD/肺气肿，这表明疾病背后的慢性炎症在很大程度上是由遗传因素决定的。由于COPD/肺气肿的诊断通常是在晚期，当不可逆转的肺破坏导致肺功能和生活质量显著受损时，需要在COPD/肺气肿病程早期出现的严重肺部疾病的标志物，这些标志物可以用来预测肺功能的迅速丧失。我们以前已经证明肺气肿与自身免疫的CD4+T细胞和B细胞针对肺的主要结构基质蛋白弹性蛋白的反应有关。此外，辅助型T细胞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，吸烟者中T细胞和B细胞的特异性抗弹性蛋白反应可能是以后肺破坏的有价值的指标，但目前尚不清楚这些炎性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。MiRNAs是一种21个核苷酸的RNA转录本，与mRNAs的3‘非翻译区(UTR)结合，抑制蛋白质翻译。已知的大约460个人类miRNAs在白血病、前列腺癌、银屑病等慢性炎症性疾病中的独特表达模式，已被证明与临床显著预后相关。我们假设，肺miRNAs和密切相关的piRNAs的独特表达模式与抗弹性蛋白自身免疫的炎症标记物相关。此外，我们假设肺气肿的肺miRNA标志物可在同一个体的外周血液中重现，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，我们将在人类肺和外周血单核细胞短转录本中建立初步的miRNA和piRNA特征，以表征吸烟诱导的COPD/肺气肿；确定控制人类吸烟诱导的COPD/肺气肿的miRNA依赖的调控途径；并确定表征人类Th1和Th17细胞的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)