The goal of this project is to determine how fibroblast growth factors (FGFs) act individually or in concert with pattern-related genes to influence lung pattern formation and epithelial cell dedifferentiation during lung development. We will focus specifically on members of the FGF family and receptors (FGFRs), and we will study their relationship to pattern-related molecules of the Hox gene family and Sonic hedgehog (Shh), as they interact to regulate airway branching and epithelial cell differentiation in the embryonic lung. These genes are all expressed in the developing lung, and likely play an important, interactive role in lung development. We hypothesize that FGFs, Shh and Hox genes form a network of signals that results in regional control of lung patterning and epithelial differentiation. We will examine their interactions using both in vitro and in vivo model systems that include lung organ cultures, cell culture systems and transgenic animals. We propose three specific aims: (1) to study how FGFs and receptors regulate embryonic lung epithelial cell proliferation and differentiation. This will be accomplished by performing a careful evaluation of the timing and sites of FGF/FGFR expression during lung development, determining regional differences in response to exogenous FGFs (pattern of growth and differentiation) on mesenchyme-free lung and tracheal epithelial cultures, and by blocking specific FGF- FGFR interactions in cultured embryonic lung buds and in lungs of transgenic animals; (2) to determine the extent of FGF interactions with Hox genes and their role in lung development;; (3) to explore the role of Shh by overexpressing or blocking Shh in epithelial lung organ cultures, cell culture and in transgenic animals. We will study how Shh influences FGF and Hox gene expression in these systems. We will also study how pattern formation and differentiation are altered by changes in Shh expression in vitro and in vivo. These studies will provide new information about key regulatory events in epithelial-mesenchymal interactions that guide development of the embryonic lung.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL047049-09
Application #
6324748
Study Section
Project Start
2000-07-01
Project End
2001-06-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
9
Fiscal Year
2000
Total Cost
$330,327
Indirect Cost
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Mori, Munemasa; Mahoney, John E; Stupnikov, Maria R et al. (2015) Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development 142:258-67
Tagne, Jean-Bosco; Mohtar, Omar R; Campbell, Joshua D et al. (2015) Transcription factor and microRNA interactions in lung cells: an inhibitory link between NK2 homeobox 1, miR-200c and the developmental and oncogenic factors Nfib and Myb. Respir Res 16:22
Cushing, Leah; Costinean, Stefan; Xu, Wei et al. (2015) Disruption of miR-29 Leads to Aberrant Differentiation of Smooth Muscle Cells Selectively Associated with Distal Lung Vasculature. PLoS Genet 11:e1005238
Cushing, Leah; Jiang, Zhihua; Kuang, Pingping et al. (2015) The roles of microRNAs and protein components of the microRNA pathway in lung development and diseases. Am J Respir Cell Mol Biol 52:397-408
Mahoney, John E; Mori, Munemasa; Szymaniak, Aleksander D et al. (2014) The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors. Dev Cell 30:137-50
Jiang, Zhihua; Cushing, Leah; Ai, Xingbin et al. (2014) miR-326 is downstream of Sonic hedgehog signaling and regulates the expression of Gli2 and smoothened. Am J Respir Cell Mol Biol 51:273-83
Guha, Arjun; Vasconcelos, Michelle; Zhao, Rui et al. (2014) Analysis of Notch signaling-dependent gene expression in developing airways reveals diversity of Clara cells. PLoS One 9:e88848
Jean, Jyh-Chang; George, Elizabeth; Kaestner, Klaus H et al. (2013) Transcription factor Klf4, induced in the lung by oxygen at birth, regulates perinatal fibroblast and myofibroblast differentiation. PLoS One 8:e54806
Tagne, Jean-Bosco; Gupta, Sumeet; Gower, Adam C et al. (2012) Genome-wide analyses of Nkx2-1 binding to transcriptional target genes uncover novel regulatory patterns conserved in lung development and tumors. PLoS One 7:e29907
Sommer, Cesar A; Christodoulou, Constantina; Gianotti-Sommer, Andreia et al. (2012) Residual expression of reprogramming factors affects the transcriptional program and epigenetic signatures of induced pluripotent stem cells. PLoS One 7:e51711

Showing the most recent 10 out of 92 publications