Abstract

Revised Abstract: Pulmonary surfactant maintains the integrity of the alveoli by reducing surface tension at the alveolar air-tissue interface and plays important roles in host defense and inflammation in the lung. Surfactant protein B (SP-B), a hydrophobic protein of surfactant, is essential for the surface tension reducing function of surfactant. Inadequate production of SP-B leads to the development of newborn respiratory distress syndrome (newborn RDS) in premature infants. Reduced SP-B levels and increased nitric oxide (NO) production in the lung are associated with acute respiratory distress syndrome (ARDS) and acute pulmonary infections. NO is clinically used to treat a variety of lung disorders in adults and infants. Thus the respiratory epithelium can be exposed to elevated levels of endogenous or exogenous NO that can impair its function. Elevated levels of NO can adversely affect SP-B gene expression in the lung contributing to lung injury. The long-term objectives of this proposal are to elucidate molecular mechanisms that mediate nitric oxide inhibition of SP-B gene expression in lung H441 cells.
In Specific Aim 1, a. cis-DNA elements and interacting transcription factors that mediate nitric oxide inhibition of human SP-B promoter activity will be identified, b. Molecular mechanisms underlying reduced DNA binding activities of TTF-1 and HNF-3 factors in NO treated H441 cells will be investigated.
In Specific Aim 2, a. the involvement of MEK/ERK and PI3-K signaling pathways in mediating nitric oxide inhibition of SP-B gene expression will be analyzed, b. the involvement of TTF-1 and HNF-3 factors as targets for MEK/ERK and PI3-K pathways, respectively, to mediate transcriptional repression of SP-B gene expression will be investigated. The proposed studies should provide significant new information on molecular mechanisms that mediate nitric oxide inhibition of SP-B gene expression. Such information may facilitate the development of newer therapies to treat lung dysfunction due to SP-B deficiency that occurs under conditions of elevated nitric oxide production in the lung.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048048-12
Application #
6905548
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Denholm, Elizabeth M
Project Start
1993-01-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
12
Fiscal Year
2005
Total Cost
$229,218
Indirect Cost

  Institution

Name
University of Texas Health Center at Tyler
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772337
City
Tyler
State
TX
Country
United States
Zip Code
75708

  Publications

Gong, J; Nishimura, K K; Fernandez-Rhodes, L et al. (2018) Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI. Int J Obes (Lond) 42:384-390
Wang, Heming; Choi, Yoonha; Tayo, Bamidele et al. (2017) Genome-wide survey in African Americans demonstrates potential epistasis of fitness in the human genome. Genet Epidemiol 41:122-135
Fernández-Rhodes, Lindsay; Gong, Jian; Haessler, Jeffrey et al. (2017) Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. Hum Genet 136:771-800
Lee, Ju-Mi; Colangelo, Laura A; Schwartz, Joseph E et al. (2016) Associations of cortisol/testosterone and cortisol/sex hormone-binding globulin ratios with atherosclerosis in middle-age women. Atherosclerosis 248:203-9
Manichaikul, Ani; Wang, Xin-Qun; Zhao, Wei et al. (2016) Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis. J Lipid Res 57:433-42
Schreiner, Pamela J (2016) Emerging Cardiovascular Risk Research: Impact of Pets on Cardiovascular Risk Prevention. Curr Cardiovasc Risk Rep 10:
Topless, Ruth K; Flynn, Tanya J; Cadzow, Murray et al. (2015) Association of SLC2A9 genotype with phenotypic variability of serum urate in pre-menopausal women. Front Genet 6:313
Shetty, Priya B; Tang, Hua; Feng, Tao et al. (2015) Variants for HDL-C, LDL-C, and triglycerides identified from admixture mapping and fine-mapping analysis in African American families. Circ Cardiovasc Genet 8:106-13
Auer, Paul L; Nalls, Mike; Meschia, James F et al. (2015) Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. JAMA Neurol 72:781-8
Hansen, J G; Gao, W; Dupuis, J et al. (2015) Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study. Respir Res 16:81

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