Abstract

Studies of the molecular embryology of the lung are likely to provide significant new understanding of the molecular mechanisms of lung development, injury and disease. We have demonstrated that TGF-beta receptor-mediated autocrine/paracrine signaling negatively regulates early lung development. The recent identification of the Smad family signal transducer proteins has unraveled new mechanisms by which TGF-beta signals from the cell membrane to the nucleus, and our preliminary data show that Smad-mediated signaling modulates mouse lung branching morphogenesis and cytodifferentiation. Hypothesis: Specific Smad gene expression regulates TGF-beta signaling, and thus instructs early mouse embryonic lung branching morphogenesis.
Specific Aims :
Aim 1. To define the developmental and temporo-spatial expression of Smad genes during embryonic lung development (i) in vivo and (ii) in lung explant culture.
Aim 2. To determine the molecular mechanism of TGF-beta pathway- restricted Smad2 and Smad3 in regulating embryonic pulmonary branching morphogenesis and cytodifferentiation in serumless culture using both (i) """"""""loss-of-function"""""""" and (ii) """"""""gain-of- function"""""""" strategies.
Aim 3. To define the biological function of the feedback inhibitory Smad6 and Smad7 proteins during embryonic lung branching morphogenesis in culture. (i) Time- and dose-dependent TGF-beta-induced inhibitory Smad6 and Smad7 gene expression patterns will be delineated in lung explant culture. (ii) The antagonistic mechanism by inhibitory Smad6 and Smad7 on TGF-beta signaling during lung development will be determined in embryonic lung culture. Novel molecular mechanisms to control lung morphogenesis and significance to human health: The current proposal will define novel molecular mechanisms in which Smad-mediated signaling regulates embryonic lung branching morphogenesis. The results of this project will provide new rationales for novel therapeutic strategies to modulate TGF-beta signaling during lung development, injury, repair, and disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061286-01A1
Application #
2899540
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1999-08-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Sun, Jianping; Zhuang, Feng-Feng; Mullersman, Jerald E et al. (2006) BMP4 activation and secretion are negatively regulated by an intracellular gremlin-BMP4 interaction. J Biol Chem 281:29349-56
Chen, Hui; Sun, Jianping; Buckley, Sue et al. (2005) Abnormal mouse lung alveolarization caused by Smad3 deficiency is a developmental antecedent of centrilobular emphysema. Am J Physiol Lung Cell Mol Physiol 288:L683-91
Chen, Cheng; Chen, Hui; Sun, Jianping et al. (2005) Smad1 expression and function during mouse embryonic lung branching morphogenesis. Am J Physiol Lung Cell Mol Physiol 288:L1033-9
Shi, Wei; Chen, Hui; Sun, Jianping et al. (2004) Overexpression of Smurf1 negatively regulates mouse embryonic lung branching morphogenesis by specifically reducing Smad1 and Smad5 proteins. Am J Physiol Lung Cell Mol Physiol 286:L293-300
Buckley, S; Shi, W; Driscoll, B et al. (2004) BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells. Am J Physiol Lung Cell Mol Physiol 286:L81-6
Shi, Wei; Chen, Hui; Sun, Jianping et al. (2003) TACE is required for fetal murine cardiac development and modeling. Dev Biol 261:371-80
Zhao, Jingsong; Shi, Wei; Wang, Yan-Ling et al. (2002) Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol 282:L585-93
Zhao, J; Chen, H; Peschon, J J et al. (2001) Pulmonary hypoplasia in mice lacking tumor necrosis factor-alpha converting enzyme indicates an indispensable role for cell surface protein shedding during embryonic lung branching morphogenesis. Dev Biol 232:204-18
Zhao, J; Chen, H; Wang, Y L et al. (2001) Abrogation of tumor necrosis factor-alpha converting enzyme inhibits embryonic lung morphogenesis in culture. Int J Dev Biol 45:623-31
Zhao, J; Shi, W; Chen, H et al. (2000) Smad7 and Smad6 differentially modulate transforming growth factor beta -induced inhibition of embryonic lung morphogenesis. J Biol Chem 275:23992-7

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