This is a competing renewal of a Program Project Grant, currently in its 16th year, which focuses on the molecular regulation of lung development. The program has been highly successful in bringing together an interactive multidisciplinary team of investigators to explore this theme, and has resulted in significant contributions to the field. This renewal consists of five interactive projects to study determinants of cell fate and differentiation in the developing lung. These projects address critical and poorly understood issues on the mechanisms of establishment of lung cell lineages, and on how this relates to morphogenesis and acquisition of differentiated cellular phenotypes. Project 1 addresses questions related to how the initial respiratory lineages are spatially organized and expanded during early morphogenesis, and the role of Notch and Fgfs in this process. Project 2 will focus on the mechanisms by which endogenous microRNAs control dynamic gene activity during proximal-distal specification of the lung. Project 3 develops new tools exploring a mouse ES cell culture system to study the genetic mechanisms that control early lung lineage specification. Project 4 focuses on mechanisms of chromatin remodeling and DNA methylation in the regulation of gene transcription during early lung development. Project 5 examines how hematopoletic-derived cells contribute to the development of lung structure and to the establishment of native immunity. Besides these projects, three cores are proposed. The "Administrative Core" will deal with the overall management and financial aspects of the Program. The "Microscopy-Image Analysis and FACS Core" will provide resources for histology, analysis of gene/protein expression by standard or confocal microscopy and for cell sorting: The "Mouse Core" will support the investigators in maintaining the various existing mouse lines, breeding, genotyping, and for designing constructs of new mouse lines. The projects and cores are designed to be highly interactive, with extensive sharing of expertise, reagents and model systems. Results from these studies will provide relevant insights into mechanisms of lung development and stem cell biology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL047049-20
Application #
8214601
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Lin, Sara
Project Start
1998-07-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
20
Fiscal Year
2012
Total Cost
$2,458,452
Indirect Cost
$946,292
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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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
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
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Longmire, Tyler A; Ikonomou, Laertis; Hawkins, Finn et al. (2012) Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell 10:398-411
Jiang, Zhihua; Yu, Nan; Kuang, Pingping et al. (2012) Trinucleotide repeat containing 6a (Tnrc6a)-mediated microRNA function is required for development of yolk sac endoderm. J Biol Chem 287:5979-87
Ikonomou, Laertis; Hemnes, Anna R; Bilousova, Ganna et al. (2011) Programmatic change: lung disease research in the era of induced pluripotency. Am J Physiol Lung Cell Mol Physiol 301:L830-5
Christodoulou, Constantina; Longmire, Tyler A; Shen, Steven S et al. (2011) Mouse ES and iPS cells can form similar definitive endoderm despite differences in imprinted genes. J Clin Invest 121:2313-25
Tsao, Po-Nien; Wei, Shu-Chen; Wu, Ming-Fang et al. (2011) Notch signaling prevents mucous metaplasia in mouse conducting airways during postnatal development. Development 138:3533-43
Chen, Felicia; Cao, Yuxia; Qian, Jun et al. (2010) A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium. J Clin Invest 120:2040-8

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