Circulating immunoactive small RNAs in COPD as biomarkers.

PROJECT SUMMARY The overall goal of the application is to characterize the expression pattern of a novel class of circulating short non-coding RNAs (sncRNAs) in chronic obstructive pulmonary disease (COPD) using biospecimens available from the Biological Specimen and Data Repository Information Coordinating Center (BioLINCC). COPD is the most prevalent lung disease worldwide and ranks as the sixth leading cause of death in the United States. COPD is primarily caused by cigarette smoking and long-term exposure to harmful substances. Patients gradually develop the symptoms over time, lacking the opportunity for early diagnosis and timely intervention. Therefore, discovering early markers can be expected to prevent the progression to a life-threatening condition. We recently discovered novel circulating short non-coding RNAs (sncRNAs) that are upregulated in plasma obtained from patients with COPD. These RNAs are derived from 5′-half regions of tRNAValCAC and tRNAHisGUG. We demonstrated that these tRNA-derived sncRNAs activate human macrophages leading to cytokine productions, designating them as immunoactive RNAs, immR-Val and immR-His. Due to the high specificity of immR expression in patients, they hold potential for use as early diagnostic biomarkers for immRs and as inflammatory mediators associated with the progression of the disease. This previous study was conducted with a small cohort, to gain a comprehensive understanding of the expression profiles of immRs associated with COPD pathogenesis, it is imperative to use a larger number of clinically validated samples. We will obtain plasma samples from the Subpopulations and Intermediate Markers in COPD Study (SPIROMICS), a nationwide study of COPD that involves the mass collection of biospecimens. In this proposal, with over 300 plasma subjects, we will quantify the levels of immR-Val and immR-His by using our original method of TaqMan-based qPCR that allows a specific detection of target immRs from a trace amount of input RNA (Aim 1). The samples are classified into four categories based on a GOLD (Global Initiative for Obstructive Lung Disease) criteria, and we will assess whether the expression profiles of immRs are evident with the GOLD classification (Aim 2). In addition to this, we will stratify the immRs expressions based on the other patient characteristics, including age, gender, COPD severity, cigarette smoking status (duration of smoking, frequency, whether they are current smokers or have ceased smoking), and clinical parameters (BMI, duration since being diagnosed with COPD, spirometry results, medication history, and frequency of exacerbation). Our objective is to develop a comprehensive understanding of immRs through the proposed aims, providing robust evidence demonstrating the clinical associations of immRs with COPD pathogenesis.