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性肺病的免疫病理学基础。该提案特别旨在了解microRNA（miRNA）和piwi相互作用蛋白RNA（转座子沉默RNA;皮尔纳）特征在以慢性阻塞性肺病（慢性阻塞性肺病; COPD）和肺实质损失（肺气肿）为标志的吸烟相关肺病中的意义。烟草烟雾引起的慢性阻塞性肺病/肺气肿现在是工业化世界的第四大死亡原因，预计不久将成为第三大死亡原因。尽管戒烟，但所有吸烟者中的一部分最终会发展为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COPD/肺气肿病程早期出现并可用于预测肺功能快速丧失的重度肺病标志物。我们先前已经证明肺气肿与针对肺的主要结构基质蛋白弹性蛋白的自身免疫性CD 4 + T细胞和B细胞应答相关。此外，辅助性T细胞1型（Th 1）诱导的趋化因子，包括CXCL 10，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细胞以及B细胞的特异性抗弹性蛋白反应是后期肺破坏的潜在有价值的指标，但仍不清楚这些炎症标志物是否在无症状吸烟者中足够早地发展以提供临床有用的预测。miRNA是21 nt的RNA转录物，其结合于mRNA的3'非翻译区（UTR）以抑制蛋白质翻译。在白血病、前列腺癌、慢性炎症性疾病如银屑病等多种疾病中，约460种已知人类miRNA的独特表达模式先前已显示与临床显著结果相关。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志物相关。此外，我们假设肺气肿的肺miRNA标记物在相同个体的外周血中重现，并且可以用于预测自身免疫功能障碍的发作。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表征吸烟诱导的COPD/肺气肿的主要miRNA和皮尔纳特征;鉴定控制人吸烟诱导的COPD/肺气肿的miRNA依赖性调控途径;并确定表征人Th 1和Th 17细胞的miRNA和皮尔纳关系。(End摘要）

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)