Pulmonary surfactant maintains the integrity of alveoli by reducing surface tension at the alveolar air-tissue interface. Surfactant protein B (SP-B) is essential for the maintenance of biophysical properties and physiological function of surfactant. Inadequate synthesis of SP-B that occurs in premature infants is associated with the development of newborn respiratory distress syndrome (RDS) and deficiency of SP-B leads to the development of fatal respiratory failure in infants with congenital alveolar proteinosis. Deficiency of SP-B is also found in adult respiratory distress syndrome (ARDS). SP-B mRNA is expressed in a cell type-specific manner in the lung and is developmentally regulated. Glucocorticoids and cAMP induce expression of SP-B mRNA while tumor necrosis factor-alpha (TNF-alpha) inhibits expression of SP- B mRNA. The long-term objectives of this proposal are to elucidate molecular mechanisms that regulate SP-B gene expression.
In Specific Aim 1, transcriptional activators binding to a novel regulatory cis-DNA element in SP-B promoter will be purified by use of sequence-specific DNA affinity chromatography and cDNAs encoding transcriptional activators will be cloned. The cDNAs will be characterized and their role in SP-B promoter function will be analyzed by reconstituted in vitro transcription assay and cotransfection experiments.
In Specific Aim 2, the role of stereospecific alignments between various regulatory cis-DNA elements in SP-B promoter function will be analyzed by altering the helical phasing of individual elements. The role of cooperative interactions between cis-DNA elements and transcriptional activators bound to the DNA elements in SP-B promoter function will be analyzed by in vitro DNA binding studies and cotransfection experiments.
In Specific Aim 3, cis-DNA elements and transcriptional activators that mediate TNF-alpha down regulation of SP-B promoter activity will be identified and mechanisms underlying down regulation of promoter activity will be studied.
In Specific Aim 4, SP-B genomic regions that control cell-specific, developmental and multifactorial regulation of SP-B gene expression in vivo will be identified by development of transgenic mice. The studies described should provide significant new information on molecular mechanisms that control SP-B gene expression, and may aid in the development of newer therapies aimed at prevention and treatment of newborn respiratory distress syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048048-09
Application #
6389204
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Garfinkel, Susan J
Project Start
1993-01-01
Project End
2003-06-30
Budget Start
2001-04-01
Budget End
2003-06-30
Support Year
9
Fiscal Year
2001
Total Cost
$196,424
Indirect Cost
Name
University of Texas Health Center at Tyler
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
City
Tyler
State
TX
Country
United States
Zip Code
75708
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