Let-7b in BPD

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).

Grant Number: 5R01HL156275-04
NIH Institute/Center: NIH
Principal Investigator: Namasivayam Ambalavanan