Molecular Phenotypes for Lung Diseases

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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)