Bronchopulmonary dysplasia, BPD is characterized by alveolar hypoplasia & vascular abnormalities, thought to result from arrested distal lung morphogenesis. TNF-alpha & TGF-beta may play key roles in pathogenesis of BPD, but their mechanistic linkages to structural lung defects have remained elusive. We found abundant TNF-alpha & TGF-beta in the lungs of preterm infants at risk for BPD. TGF-beta, through SMAD3, interferes with NKX2.1 activity, which is strictly required for normal lung morphogenesis, cell differentiation & surfactant protein (SP), gene expression. We also found that TNF-alpha, through NF-kB, RelA (p65) represses Bmp4 transcription, another central distal lung morphoregulatory molecule. The purpose of this application is to carefully examine the interactions between mediators of injury & those of morphogenesis in the fetal and neonatal lung. Hypothesis: Mediators of injury, TGF-beta-activated SMAD3 & TNF-alpha-activated NF-kB interfere with normal lung development & result in pathogenesis of BPD. This hypothesis is supported by the available data & some of its predictions are directly testable by the following specific aims:
Specific Aim 1. To determine whether, & to what extent, neonatal Smad3(-/-) mice are protected against hyperoxia, virally delivered TGF-beta, and LPS-induced alveolar hypoplasia? Specific Aim 2. To determine whether SMAD3 mediates TGF-beta-induced repression of SpB transcription in vivo.
Specific aim 3. To determine the precise mechanisms by which SMAD3 represses the activity of NKX2.1.
Specific aim 4 : To determine the mechanism by which TNF-alpha represses Bmp4 gene expression.
Specific aim 5. To determine the role of RelA in morphogenesis & pathogenesis of neonatal lung. By the completion of the goals outlined above, a more mechanistic understanding of interactions between mediators of injury & lung development, in the context of BPD should emerge. We hope that this understanding would fuel novel ways of countering BPD in human premies.
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