Summary
This project investigates microRNA let-7b-5p as a robust biomarker for bronchopulmonary dysplasia (BPD) in extremely low birth weight infants and its role in lung development and angiogenesis.
Let-7b in BPD
US · IL
National Heart Lung and Blood Institute
grant
open
#nih-5R01HL156275-03
What they want
The project will test central hypotheses that let-7b-5p is a valuable biomarker for BPD staging, progression, and therapy response; is released from airway epithelial cells by oxidative stress; contributes to dysregulated angiogenesis in BPD; and that its inhibition improves lung angiogenesis and attenuates the BPD phenotype. This will be achieved through three specific aims: 1) measuring plasma let-7b-5p in serial samples from 150 extremely preterm infants to track lung disease progression and therapy response, 2) determining mechanisms of let-7b release by newborn mouse lung airway epithelium using novel transgenic mice and cell culture models, and 3) determining effects of excessive let-7b-5p signaling on lung microvascular development using newborn mouse models.
Deliverables
- Defined temporal changes in let-7b-5p with respiratory illness severity, BPD staging, lung mechanics, and clinical therapies
- Confirmation of oxidative stress as a key upstream mechanism for let-7b-5p release
- Determination of the role of Nrf2 and NF-kB signaling in let-7b-5p release
- Determination of effects of excessive let-7b-5p signaling on lung microvascular development
- Evidence that inhibition of let-7b-5p improves lung development in hyperoxia-exposed newborn mouse lung
Technical requirements
- Measurement of let-7b-5p in serial plasma samples
- Use of a well-characterized prospective cohort of 150 extremely preterm infants
- Use of novel transgenic mice
- Testing the hypothesis that reduction of mitochondrial ROS reduces let-7b-5p and the BPD phenotype
- Determination of the role of Nrf2 and NF-kB signaling using specific inhibitors/modulators in cell culture models
- Over-expression of let-7b-5p to induce impaired lung microvascular development in newborn mice
- Inhibition of let-7b-5p in hyperoxia-exposed newborn mouse lung (BPD model)
