Bronchopulmonary dysplasia, BPD, is characterized by alveolar hypoplasia, thought to result from arrested distal lung morphogenesis. Currently, inflammation and pro-fibrotic growth factors, such as TGF-beta, are deemed as major causes of injury. In human premature neonates, lung TGF-beta correlates with severity of BPD. The current project proposes to examine the role of TGF-beta within the context of the following hypothesis: Hypothesis: Mediators of injury and in particular the TGF-beta1-activated SMAD3 interfere with normal developmental pathways & result in pathogenesis of BPD. To test the above hypothesis, we propose three Specific Aims:
Specific aim 1. To determine whether, and to what extent, neonatal Smad3(-/-) mice are protected against hyperoxia-, or virally delivered TGF-beta1-induced alveolar hypoplasia? Specific aim 2. To determine whether explanted embryonic Smad3(-/-) lungs are protected against pathological role of TGF-beta1? Specific aim 3. To determine whether conditional overexpression of Smad3 causes structural abnormalities and null or partial SP-B deficiency in perinatal and postnatal transgenic mice? Significance: Interplay between injury and normal lung morphogenesis is thought to be etiologic of BPD. This project presents a unique opportunity to elucidate precisely how TGF-beta, as a known mediator of injury, disrupts lung morphogenesis by affecting, through SMAD3, the normal function of key morphoregulatory transcription factors such as NKX2.1.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL073471-01A1
Application #
6722480
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Berberich, Mary Anne
Project Start
2003-12-15
Project End
2008-11-30
Budget Start
2003-12-15
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$324,417
Indirect Cost
Name
University of Southern California
Department
Pediatrics
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Xing, Yiming; Wang, Runming; Li, Changgong et al. (2015) PTEN regulates lung endodermal morphogenesis through MEK/ERK pathway. Dev Biol 408:56-65
Zhou, Beiyun; Ann, David K; Flodby, Per et al. (2008) Rat aquaporin-5 4.3-kb 5'-flanking region differentially regulates expression in salivary gland and lung in vivo. Am J Physiol Cell Physiol 295:C111-20
De Langhe, Stijn P; Carraro, Gianni; Tefft, Denise et al. (2008) Formation and differentiation of multiple mesenchymal lineages during lung development is regulated by beta-catenin signaling. PLoS One 3:e1516
Zhou, Beiyun; Francis, Tricia A; Yang, Hui et al. (2008) GATA-6 mediates transcriptional activation of aquaporin-5 through interactions with Sp1. Am J Physiol Cell Physiol 295:C1141-50
Xing, Yiming; Li, Changgong; Hu, Lingyan et al. (2008) Mechanisms of TGFbeta inhibition of LUNG endodermal morphogenesis: the role of TbetaRII, Smads, Nkx2.1 and Pten. Dev Biol 320:340-50
Zhou, Beiyun; Zhong, Qian; Minoo, Parviz et al. (2008) Foxp2 inhibits Nkx2.1-mediated transcription of SP-C via interactions with the Nkx2.1 homeodomain. Am J Respir Cell Mol Biol 38:750-8
Flodby, Per; Zhou, Beiyun; Ann, David K et al. (2007) Conserved elements within first intron of aquaporin-5 (Aqp5) function as transcriptional enhancers. Biochem Biophys Res Commun 356:26-31
Ramasamy, Suresh K; Mailleux, Arnaud A; Gupte, Varsha V et al. (2007) Fgf10 dosage is critical for the amplification of epithelial cell progenitors and for the formation of multiple mesenchymal lineages during lung development. Dev Biol 307:237-47
Zhou, Beiyun; Ann, David K; Li, Xian et al. (2007) Hypertonic induction of aquaporin-5: novel role of hypoxia-inducible factor-1alpha. Am J Physiol Cell Physiol 292:C1280-90