The long-term goals of this work are to study the functional roles of nuclear receptor co-activators in mediating signaling pathways critical to lung development and surfactant protein B (SP-B) gene expression in respiratory epithelial cells. Co-activators including p160 family members (SRC-1, ACTR and TIF2) and CBP/p300 possess histone acetyltransferase (HAT) activity and are known to play important roles in gene activation, cell differentiation and proliferation. The state of the art approaches of biochemical/molecular biology and conditional transgenic mouse models will be utilized.
The specific aims are: 1): Characterization of SP-B chromatin acetylation in H441 cells to test hypothesis that histones in the SP-B promoter/enhancer region are hyperacetylated during transcriptional activation. Chromatin cross-linking and chromatin immunoprecipitation (CHIP) assays will be performed; 2): Characterization of trans-interactions between nuclear receptor coactivators and TTF-1 to test hypothesis that nuclear receptor co-activators interact directly with TTF-1 to control target SP-B gene expression. Co-immunoprecipitation, Western blot, GST pulldown and mammalian two-hybrid system will be performed to identify the precise interacting domains of both nuclear receptor co-activators and TTF-1; 3): Characterization of TTF-1 acetylation by nuclear receptor co-activators to test hypothesis that nuclear receptor co-activators acetylate TTF-1 in lung epithelial cells. Specific nuclear receptor co-activators (e.g. SRC-1, ACTR, CBP/p300) acetylating TTF-1 will be identified. The precise acetylated lysine residues on TTF-1 will be identified by domain mapping and site-specific mutagenesis; 4): Characterization of dominant negative RAR in doxycycline-regulatable transgenic mice to test hypothesis that nuclear receptor co-activators are critical to lung development and recovery/remodeling of respiratory epithelial cells from emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067862-02
Application #
6773854
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Berberich, Mary Anne
Project Start
2003-07-07
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$372,500
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Yan, Cong; Qu, Peng; Du, Hong (2012) Myeloid-specific expression of Stat3C results in conversion of bone marrow mesenchymal stem cells into alveolar type II epithelial cells in the lung. Sci China Life Sci 55:576-90
Wu, Lingyan; Yan, Cong; Czader, Magdalena et al. (2012) Inhibition of PPAR? in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis. Blood 119:115-26
Kirov, Aleksandr; Duarte, Maria; Guay, Justin et al. (2012) Transgenic expression of nonclassically secreted FGF suppresses kidney repair. PLoS One 7:e36485
Wu, Lingyan; Wang, Guixue; Qu, Peng et al. (2011) Overexpression of dominant negative peroxisome proliferator-activated receptor-? (PPAR?) in alveolar type II epithelial cells causes inflammation and T-cell suppression in the lung. Am J Pathol 178:2191-204
Li, Yuan; Qu, Peng; Wu, Lingyan et al. (2011) Api6/AIM/Spýý/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma. Cancer Res 71:5488-99
Qu, Peng; Yan, Cong; Blum, Janice S et al. (2011) Myeloid-specific expression of human lysosomal acid lipase corrects malformation and malfunction of myeloid-derived suppressor cells in lal-/- mice. J Immunol 187:3854-66
Qu, Peng; Yan, Cong; Du, Hong (2011) Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis. Blood 117:4476-89
Qu, Peng; Shelley, William C; Yoder, Mervin C et al. (2010) Critical roles of lysosomal acid lipase in myelopoiesis. Am J Pathol 176:2394-404
Qu, Peng; Roberts, Jennifer; Li, Yuan et al. (2009) Stat3 downstream genes serve as biomarkers in human lung carcinomas and chronic obstructive pulmonary disease. Lung Cancer 63:341-7
Qu, Peng; Du, Hong; Wilkes, David S et al. (2009) Critical roles of lysosomal acid lipase in T cell development and function. Am J Pathol 174:944-56

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