Pulmonary surfactant stabilizes alveoli by reducing surface tension at the alveolar air-liquid interface. Deficient production of surfactant is the major cause of respiratory distress syndrome (RDS) of the newborn. Surfactant protein B(SP-B) plays a major role in prevention of alveolar collapse by enhancing the surface active properties of surfactant phospholipids. It is the objective of this proposal to elucidate molecular mechanisms that mediate cell-specific, developmental, and hormonal regulation of expression of rabbit SP-B gene.
The specific aims of the proposal are 1. Characterization of SP-B cDNA and investigation of molecular mechanisms that mediate tissue-specific and developmental regulation of SP-B gene expression. 2. Investigation of molecular mechanisms that mediate cAMP and glucocorticoid dependent induction of SP-B gene expression in fetal lung in vitro. 3. Isolation and characterization of SP-B gene and identification of cis-acting DNA sequences required for cell-specific and cAMP and glucocorticoid regulation. 4. Identification of putative trans-acting factors of SP-B gene and purification of trans-acting factor(s) required for cell- specific expression. Northern hybridization analysis of RNA and transcription run-on assays will be utilized to define the role of transcriptional and posttranscriptional mechanisms in the developmental, and cAMP and glucocorticoid regulation of SP-B gene expression. The role of chromatin structure in mediating cell-specific, and developmental regulation of SP- B gene expression will be analyzed by DNase I hypersensitivity studies of chromatin. Cis-acting DNA regulatory elements of SP-B gene will be identified by transfection and transient expression analysis of chimeric genes that contain 5' flanking DNA sequences of SP-B gene fused to CAT gene. Trans-acting factors of SP-B gene will be identified by DNase I footprinting, gel retardation and Southwestern blotting analysis of nuclear proteins of lung tissues. Cell specific trans-acting factor(s) will be purified by means of DNA-sequence specific affinity chromatography and their role in the transcriptional regulation of SP-B gene will be investigated using an in vitro reconstituted transcription assay system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29HL048048-01A1
Application #
3473807
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1993-01-01
Project End
1997-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Health Center at Tyler
Department
Type
Other Domestic Higher Education
DUNS #
City
Tyler
State
TX
Country
United States
Zip Code
75708
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
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
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
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

Showing the most recent 10 out of 169 publications