Lung immaturity is a major cause of morbidity in premature infants and lung diseases affect millions every year. This grant addresses how lung development is controlled by the Nuclear Factor I B transcription factor (NFIB) and other NFI family members. We have shown that disruption of Nfib causes perinatal lethality in mice due to a failure in lung maturation. We hypothesize that Nfib expression in lung mesenchyme is essential for lung maturation. To test this hypothesis we will: 1) Identify target genes of Nfib needed for mouse lung maturation. Nfib knockout (KO) mice die at birth due to lung immaturity. We will find the target genes of Nfib in lung maturation, assess changes in growth properties of cells from Nfib-/- lungs and determine whether the block in maturation can be overcome by glucocorticoids, a standard treatment for human fetal lung immaturity. 2) Generate a conditional knockout allele of Nfib and eliminate Nfib function separately in different cell populations in the lung, to determine in which cells Nfib is needed for lung maturation. This will directly test of hypothesis that Nfib is essential in lung mesenchyme. 3) Determine how other NFI family members cooperate with or antagonize Nfib function in lung development by making mice deleted for 2 NFI genes simultaneously, Nfib+Nfic and Nfib+Nfix. We propose that these NFI genes interact with Nfib in lung development and in the development of other organs. These studies will yield new insights into the molecular mechanisms of lung development and how they are regulated by the highly-conserved NFI transcription factor family.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080624-04
Application #
7754424
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2007-03-03
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$396,250
Indirect Cost
Name
State University of New York at Buffalo
Department
Biochemistry
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Harris, Lachlan; Zalucki, Oressia; Gobius, Ilan et al. (2016) Transcriptional regulation of intermediate progenitor cell generation during hippocampal development. Development 143:4620-4630
Mellas, R E; Kim, H; Osinski, J et al. (2015) NFIB regulates embryonic development of submandibular glands. J Dent Res 94:312-9
Vidovic, Diana; Harris, Lachlan; Harvey, Tracey J et al. (2015) Expansion of the lateral ventricles and ependymal deficits underlie the hydrocephalus evident in mice lacking the transcription factor NFIX. Brain Res 1616:71-87
Heng, Yee Hsieh Evelyn; Zhou, Bo; Harris, Lachlan et al. (2015) NFIX Regulates Proliferation and Migration Within the Murine SVZ Neurogenic Niche. Cereb Cortex 25:3758-78
Harris, Lachlan; Genovesi, Laura A; Gronostajski, Richard M et al. (2015) Nuclear factor one transcription factors: Divergent functions in developmental versus adult stem cell populations. Dev Dyn 244:227-38
Robinson, Gertraud W; Kang, Keunsoo; Yoo, Kyung Hyun et al. (2014) Coregulation of genetic programs by the transcription factors NFIB and STAT5. Mol Endocrinol 28:758-67
Heng, Yee Hsieh Evelyn; McLeay, Robert C; Harvey, Tracey J et al. (2014) NFIX regulates neural progenitor cell differentiation during hippocampal morphogenesis. Cereb Cortex 24:261-79
Grabowska, Magdalena M; Elliott, Amicia D; DeGraff, David J et al. (2014) NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression. Mol Endocrinol 28:949-64
Lajoie, Mathieu; Hsu, Yu-Chih; Gronostajski, Richard M et al. (2014) An overlapping set of genes is regulated by both NFIB and the glucocorticoid receptor during lung maturation. BMC Genomics 15:231
Dixon, Chantelle; Harvey, Tracey J; Smith, Aaron G et al. (2013) Nuclear factor one X regulates Bobby sox during development of the mouse forebrain. Cell Mol Neurobiol 33:867-73

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