Surfactant protein B (SP-B) is a 79-amino acid peptide produced in pulmonary non-ciliated bronchiolar epithelial cells (Clara cells) and alveolar type II epithelial cells. The SP-B peptide is stored in lamellar bodies and secreted with phospholipids into the airway lumen to facilitate the stability and rapid spreading of surfactant phospholipids during respiratory cycles. Null mutations in the SP-B gene cause lethal respiratory distress in newborn infants and in SP-B deficient mice produced by gene targeting. SP-B is essential for postnatal alveolar maturation and respiratory adaptation in newborns. The long-term goals of this work are to identify cis-acting DNA elements and trans-acting protein factors that control SP-B gene temporal/spatial expression in developing and mature lungs. During the last several years of study, it has been identified that retinoic acid receptor heterodimer (RAR/RXR), thyroid transcription factor 1 (TTF-1), nuclear receptor co-activators (CBP/p300 and p160 co-activators, including SRC-1, TIF2 and ACTR) and signal transducers and activators of transcription 3 (STAT3) cooperatively stimulate hSP-B transcription through an enhancer region (-500 to -331 bp). To extend the study, we will 1): characterize functional domains and amino acid residues that are involved in the interaction between RARalpha and STAT3; 2) characterize RARE and TTF-1 cis-acting sites in the hSP-B enhancer region (-500 to -331 bp) that determine hSP-B gene temporal/spatial expression in bronchiolar epithelial cells using LacZ transgenic mice; 3) characterize cis-acting elements that determine hSP-B gene temporal/spatial expression in alveolar type II epithelial cells using LacZ transgenic mice. These studies along with previous findings will lead to a better understanding of molecular basis for SP-B homeostasis in lung biology. Knowing this will help to design strategies to combat congenital and acquired respiratory diseases such as emphysema, respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD), the leading causes of mortality and morbidity in preterm infants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061803-07
Application #
6910774
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Berberich, Mary Anne
Project Start
1999-08-20
Project End
2005-09-30
Budget Start
2005-07-01
Budget End
2005-09-30
Support Year
7
Fiscal Year
2005
Total Cost
$67,050
Indirect Cost
Name
Children's Hospital Med Ctr (Cincinnati)
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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