Abstract

Our proposal focuses on the localization, migration and mechanism of differentiation of the smooth muscle progenitor cells during embryonic lung development. Fibroblast Growth factor 10 is one of the earliest genes expressed in a regionalized manner in the distal mesenchyme of the embryonic lung. Our preliminary data indicate that FGF10 plays a role in myogenesis. We therefore propose to test the following Hypothesis: progenitor cells are present in the distal mesenchyme in the embryonic lung and Fgf10 can be used as a marker to characterize them. In addition, FGF10 is involved, directly or indirectly, to maintain the smooth muscle progenitor cell population and/or to allow, via BMP4, proper differentiation of these progenitors into smooth muscle cells.
Aim 1 : To determine temporal-spatial expression of LacZ and Fgf10 in a novel Fgf10-enhancer trap mouse transgenic line.
Aim 2 : To determine the migration of distal mesenchymal cells toward the distal epithelium and the expression of smooth muscle cell differentiation markers in these cells.
Aim 3 : To determine the role of Fgf10 in the maintenance and/or differentiation of smooth muscle progenitor cells in the embryonic lung.
Aim 4 : To determine the role of Bone Morphogenetic Protein 4, a downstream epithelial target of FGF10, in controlling smooth muscle progenitor cell differentiation. Health relevance: Abnormal proliferation of the smooth muscle cells around the bronchi has been shown in several human chronic diseases such as asthma, broncho-pulmonary dysplasia and lymphangioleiomyomatosis. Our proposal may identify novel targets to control the proliferation of smooth muscle.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074832-02
Application #
6868082
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Berberich, Mary Anne
Project Start
2004-03-15
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$334,800
Indirect Cost

  Institution

Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027

  Publications

Singh, Indrabahadur; Ozturk, Nihan; Cordero, Julio et al. (2015) High mobility group protein-mediated transcription requires DNA damage marker ?-H2AX. Cell Res 25:837-50
Mukhametshina, Regina T; Ruhs, Aaron; Singh, Indrabahadur et al. (2013) Quantitative proteome analysis of alveolar type-II cells reveals a connection of integrin receptor subunits beta 2/6 and WNT signaling. J Proteome Res 12:5598-608
Al Alam, Denise; Warburton, David (2013) Wingless: developmentally important genes that respond adversely to smoking. Thorax 68:703-4
Al Alam, Denise; Sala, Frederic G; Baptista, Sheryl et al. (2012) FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. Dev Biol 369:340-8
Tiozzo, Caterina; Carraro, Gianni; Al Alam, Denise et al. (2012) Mesodermal Pten inactivation leads to alveolar capillary dysplasia- like phenotype. J Clin Invest 122:3862-72
Volckaert, Thomas; Dill, Erik; Campbell, Alice et al. (2011) Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury. J Clin Invest 121:4409-19
Sala, Frederic G; Del Moral, Pierre-Marie; Tiozzo, Caterina et al. (2011) FGF10 controls the patterning of the tracheal cartilage rings via Shh. Development 138:273-82
Al Alam, Denise; Green, Melissa; Tabatabai Irani, Reza et al. (2011) Contrasting expression of canonical Wnt signaling reporters TOPGAL, BATGAL and Axin2(LacZ) during murine lung development and repair. PLoS One 6:e23139
Rice, David P C; Connor, Elaine C; Veltmaat, Jacqueline M et al. (2010) Gli3Xt-J/Xt-J mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation. Hum Mol Genet 19:3457-67
Parsa, Sara; Kuremoto, Koh-Ichi; Seidel, Kerstin et al. (2010) Signaling by FGFR2b controls the regenerative capacity of adult mouse incisors. Development 137:3743-52

Showing the most recent 10 out of 24 publications