Monday, October 14, 2024
10/14/2024
Project Summary Bronchopulmonary dysplasia (BPD) is common in extremely low birth weight (ELBW) infants. Recently, we discovered that the strongest biomarker signal was of microRNA let-7b-5p, with a 46-fold increase (p<0.001) at birth in the blood of infants who subsequently developed severe BPD (versus no BPD) many weeks later at 36w post-menstrual age. We also found a 14-fold increase of let-7b-5p on day 1 in the tracheal aspirate of infants who subsequently developed BPD. In cell culture, airway epithelial cells were the primary source of let-7b-5p, that increased with hyperoxia. We found that excessive let-7b inhibits angiogenesis, and that let-7b inhibition during hyperoxia improves lung development in newborn mice. In the “Let-7b in BPD” project, we will build upon our exciting discovery of let-7b-5p as a robust biomarker of BPD, and determine its relevance to lung development and BPD. We will test the central hypotheses that miRNA let-7b-5p is (a) a valuable biomarker for staging, monitoring disease progression and response to therapy, (b) is released from airway epithelial cells by oxidative stress, (c) is a contributor to dysregulated angiogenesis in bronchopulmonary dysplasia, and (d) that inhibition of let-7b signaling improves lung angiogenesis and attenuates the BPD phenotype. We will test the hypotheses by the following Specific Aims: Specific Aim 1 – Determine if plasma let-7b-5p concentrations in extremely preterm infants track with lung disease progression and correlate with response to therapy. Let-7b-5p will be measured in serial plasma samples from a well characterized prospective cohort of 150 extremely preterm infants. We will define the temporal changes in let-7b-5p with respiratory illness severity, BPD staging and lung mechanics at 36w PMA, and with clinical therapies. Specific Aim 2 – Determine the mechanisms of Let-7b release by newborn mouse lung airway epithelium To confirm that the let-7b-5p release by oxidative stress is the key upstream mechanism, we will use novel transgenic mice. We will test the hypothesis that reduction of mitochondrial ROS reduces let-7b-5p and the BPD phenotype, and determine the role of Nrf2 and NF-kB signaling using specific inhibitors/modulators in cell culture models. Specific Aim 3 – Determine effects of excessive let-7b-5p signaling on lung microvascular development. We will test the hypothesis that over-expression of let-7b-5p induces impaired lung microvascular development, inducing a BPD phenotype in newborn mice even in normoxia, and that inhibition of let-7b-5p improves lung development in hyperoxia- exposed newborn mouse lung (BPD model).
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
