Early embryonic lung development, particularly early branching morphogenesis, is controlled by epithelium-mesenchyme interaction, in which autocrine/paracrine growth factors, including BMP4, are involved. This proposal is focused on determining the mechanisms by which BMP4 induces lung branching morphogenesis in mouse. Hypothesis: BMP4 induces mouse embryonic lung epithelial branching morphogenesis in a mesenchyme-dependent manner through activation of specific downstream signaling proteins.
Specific Aims :
Aim 1. To determine mesenchyme mediated inductive mechanisms of BMP4 on epithelial branching morphogenesis of E11.5 mouse embryonic lung.
Aim 2. To define gene expression pattern, specific activation, and biological function of specific BMP4 receptors and downstream Smads during BMP4 induced embryonic lung branching morphogenesis.
Aim 3. To determine the biological roles of specific negative regulators (Gremlin, NMA, and Smad6) of BMP4 signaling during embryonic lung branching morphogenesis. Health Relevance: The studies will provide fundamental knowledge about BMP4 and lung development, which will help us to better understand congenital and neonatal pulmonary diseases as well as lung injury repair. This basic information may aid in the future design of novel therapeutic strategies to prevent and treat such serious pulmonary diseases as lung hypoplasia, bronchopulmonary dysplasia and emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL068597-01
Application #
6416585
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Berberich, Mary Anne
Project Start
2002-01-01
Project End
2005-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
1
Fiscal Year
2002
Total Cost
$299,200
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Luo, Yongfeng; Chen, Hui; Ren, Siying et al. (2016) BMP signaling is essential in neonatal surfactant production during respiratory adaptation. Am J Physiol Lung Cell Mol Physiol 311:L29-38
Ren, Siying; Luo, Yongfeng; Chen, Hui et al. (2016) Inactivation of Tsc2 in Mesoderm-Derived Cells Causes Polycystic Kidney Lesions and Impairs Lung Alveolarization. Am J Pathol 186:3261-3272
Buckley, Susan; Shi, Wei; Xu, Wei et al. (2015) Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J 46:1417-29
Luo, Yongfeng; Xu, Wei; Chen, Hui et al. (2015) A novel profibrotic mechanism mediated by TGF?-stimulated collagen prolyl hydroxylase expression in fibrotic lung mesenchymal cells. J Pathol 236:384-94
Luo, Yongfeng; El Agha, Elie; Turcatel, Gianluca et al. (2015) Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development. BMC Biol 13:42
Siddique, Imad; Curran, Simon P; Ghayur, Ayesha et al. (2014) Gremlin promotes peritoneal membrane injury in an experimental mouse model and is associated with increased solute transport in peritoneal dialysis patients. Am J Pathol 184:2976-84
Zhang, Wenming; Menke, Douglas B; Jiang, Meisheng et al. (2013) Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer. BMC Biol 11:111
Xu, Wei; Liu, Chengyu; Kaartinen, Vesa et al. (2013) TACE in perinatal mouse lung epithelial cells promotes lung saccular formation. Am J Physiol Lung Cell Mol Physiol 305:L953-63
Turcatel, Gianluca; Rubin, Nicole; Menke, Douglas B et al. (2013) Lung mesenchymal expression of Sox9 plays a critical role in tracheal development. BMC Biol 11:117
Wang, Yulian; Huang, Zheping; Nayak, Pritha S et al. (2013) Strain-induced differentiation of fetal type II epithelial cells is mediated via the integrin ?6?1-ADAM17/tumor necrosis factor-?-converting enzyme (TACE) signaling pathway. J Biol Chem 288:25646-57

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