Saturday, December 21, 2024
12/21/2024
Project Summary Bronchopulmonary dysplasia (BPD), the most common complication in extremely preterm infants, is characterized by impaired lung development. Decreasing oxidant stress which plays a significant role in BPD pathogenesis remains a critical unmet need. Mitochondrial dysfunction, a known mediator of pathological oxidant stress, disrupts alveolar epithelial function and promotes lung fibrosis. Dysfunctional mitochondria generate more oxidants, exhibit impaired mitophagy, and trigger the release of pro- inflammatory mitochondrial DNA-damage associated molecular patterns (mtDNA-DAMPs) and lung injury. Furthermore, mtDNA haplogroups, which are inherited polymorphisms that vary with ethnicity, have been implicated in various lung pathologies. Our group has observed that perinatal mesenchymal stem cells (MSC) and human umbilical venous endothelial cells (HUVEC) mitochondrial dysfunction predicts BPD risk and that decreased MSC mitophagy correlates with increased BPD severity. We have also found that intranasal thyroid hormone-induced mitochondrial biogenesis is associated with decreased hyperoxic lung injury and that mtDNA haplogroups mediate differences in hyperoxia-induced mtDNA damage, inflammatory lung injury, and arrested lung development in newborn mice. In this "MtDNA Haplogroups in BPD" project, we will build on these findings and test the central hypotheses that mtDNA haplogroup variation-mediated differences in postnatal mitochondrial function, mtDNA-DAMPs and mitophagy modulate BPD risk in infants, and that TH-mediated pulmonary mitochondrial biogenesis can mitigate such differences to decrease neonatal hyperoxic lung injury through these specific aims: Specific Aim 1 Hypothesis: mtDNA haplogroups modulate BPD risk through differences in platelet bioenergetics, apoptosis, and plasma mtDNA-DAMPs in infants. Approach Determine infant mtDNA haplogroups, platelet bioenergetics, apoptosis, plasma mtDNA-DAMPs and lung injury severity (Jensen BPD status). Specific Aim 2 will test the Hypothesis that mtDNA haplogroups modulate BPD risk through differences in oxidant stress, mtDNA damage and mitophagy in infants. Approach Determine HUVEC, MSC and platelet oxidant generation, plasma oxidant stress, mtDNA damage, and mitophagy and lung injury severity. Specific Aim 3 will test the Hypothesis that thyroid hormone signaling effects mitigate mtDNA haplogroup-mediated differences in neonatal hyperoxic lung injury in mice. Approach: Expose wildtype and MNX mice to normoxia/hyperoxia and saline/TH and measure lung damage, inflammation, oxidant stress and single-cell genomic transcriptional/methylation differences.
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