The overall goal of this project is to elucidate the control of surfactant phospholipid synthesis and to determine how hormones influence this process during fetal lung development. Such information is essential for development of rational therapeutic approaches to prevention and/or control of the respiratory distress syndrome (RDS) in premature newborn humans. Although considerable progress has been made in combating RDS, it is still a major cause of morbidity and mortality among premature infants. A major focus in this application will be on the mechanisms of regulation of choline-phosphate cytidylyltransferase (CYT) - the enzyme which catalyzes the rate-limiting step in phosphatidylcholine synthesis. There is evidence that CYT activity is increased when phosphatidylcholine synthesis is increased by estrogen, glucocorticoids and thyroid hormone in fetal lung. There is also evidence that the catalytic activity rather than the amount of the enzyme is increased. We will determine whether such increase in CYT activity is mediated by phospholipids, fatty acids, intracellular translocation or dephosphorylation/phosphorylation. We will examine effects of estrogen in the fetal rabbit and those of glucocorticoids and thyroid hormone in the fetal rat. In addition, we will examine regulation of phospholipid synthesis and CYT activity in adult rat type II cells under conditions of altered phospholipid synthesis in response to cyclic AMP and phosphodiesterase inhibitors, other drugs which influence phospholipid synthesis and altered cultural conditions. We will determine how phospholipids in the culture medium stimulate phosphatidylcholine synthesis in type II cells, whether CYT activity is increased under these conditions, whether the effect is specifically on phosphatidylcholine or if other phospholipids are also affected and if other enzymes of phospholipid synthesis are stimulated. In addition to these studies, we will determine if the hormones influence rate-regulatory enzymes in the glycolytic pathway and in fatty acid synthesis. We will explore the possibility that estromedins in the circulation mediate the stimulatory effect of estrogen on fetal lung maturation. In this largely biochemical study we will use lungs from intact fetal rabbits and rats after maternal hormone administration, fetal rabbit and rat lung explants in organ culture and type II pneumocytes from the adult rat in primary culture.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD010192-11
Application #
3311241
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1976-09-30
Project End
1989-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
11
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Xu, Z X; Smart, D A; Rooney, S A (1990) Glucocorticoid induction of fatty-acid synthase mediates the stimulatory effect of the hormone on choline-phosphate cytidylyltransferase activity in fetal rat lung. Biochim Biophys Acta 1044:70-6
Rooney, S A (1989) Fatty acid biosynthesis in developing fetal lung. Am J Physiol 257:L195-201
Xu, Z X; Rooney, S A (1989) Influence of dexamethasone on the lipid distribution of newly synthesized fatty acids in fetal rat lung. Biochim Biophys Acta 1005:209-16
Kresch, M J; Smart, D A; Wilson, C M et al. (1988) Activities of enzymes of phospholipid and fatty acid synthesis in fetal and adult rat type II pneumocytes. Biochim Biophys Acta 962:173-7
Pope, T S; Smart, D A; Rooney, S A (1988) Hormonal effects on fatty-acid synthase in cultured fetal rat lung;induction by dexamethasone and inhibition of activity by triiodothyronine. Biochim Biophys Acta 959:169-77
Rosenberg, I L; Smart, D A; Gilfillan, A M et al. (1987) Effect of 1-oleoyl-2-acetylglycerol and other lipids on phosphatidylcholine synthesis and cholinephosphate cytidylyltransferase activity in cultured type II pneumocytes. Biochim Biophys Acta 921:473-80
Rooney, S A (1987) Biochemical development of the lung and regulation of surfactant secretion. Mead Johnson Symp Perinat Dev Med :12-21
Pope, T S; Rooney, S A (1987) Effects of glucocorticoid and thyroid hormones on regulatory enzymes of fatty acid synthesis and glycogen metabolism in developing fetal rat lung. Biochim Biophys Acta 918:141-8
Gilfillan, A M; Smart, D A; Rooney, S A (1986) Comparison of the enzyme activities of phosphatidylcholine, phosphatidylglycerol and phosphatidylinositol synthesis in freshly isolated type II pneumocytes and whole lung from the adult rat. Biochim Biophys Acta 877:151-7
Gross, I; Dynia, D W; Rooney, S A et al. (1986) Influence of epidermal growth factor on fetal rat lung development in vitro. Pediatr Res 20:473-7

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