The broad, long-term objective of this application is to define the role of the fetal testicular glycoprotein, Mullerian Inhibiting Substance (MIS) in prenatal lung development. Neonatal human males with respiratory distress syndrome (RDS) experience greater morbidity and mortality than females and RDS continues to be the single most important source of morbidity in babies born prematurely in industrialized countries. High serum concentrations of MIS are present in neonatal males and in several studies MIS is an inhibitor of the fetal lung.
The specific aims of this project are: (1) To isolate and purify the MIS receptor from fetal lung tissue with affinity chromatography using columns linked to MIS or anti-idiotypic antibody with application of fetal lung membranes. (2) To characterize the MIS receptor site number and binding constants using 125I-MIS and cold MIS in binding experiments on whole cells, semi-pure, and purified membrane preparations, and progressively purified MIS receptor preparations. (3) To study the mechanism of MIS action in fetal lung, MIS inhibition of EGF receptor phosphorylation will be explored to determine if MIS inhibits EGF receptor tyrosine kinase, if MIS changes the Km of EGF for its receptor or alters the Vmax or activates protein kinase C or a phosphatase. (4) To outline the fetal lung developmental expression of the MIS receptor quantitative immunoblotting with anti-idiotypic antibody to MIS, 125I-protein A, and immunoperoxidase staining will be used in fetal lung from gestational days 16-22.5. (5) To begin pilot studies on the MIS and MIS antibody effects on lung carcinomas in vitro. (6) To collect and analyze by ELISA and Western analysis over the entire granting period human neonatal serum with clinical correlations on presence-severity of lung disease; to perform immunohistochemical studies with the MIS anti-idiotypic antibody on autopsy and biopsy lung specimens to further explore the human correlation of specific MIS effects in developing lung.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Human Embryology and Development Subcommittee 1 (HED)
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Massachusetts General Hospital
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Maggard, M A; Catlin, E A; Hudson, P L et al. (1996) Reduction of epidermal growth factor receptor phosphorylation by activated Mullerian inhibiting substance is vanadate-sensitive. Metabolism 45:190-5
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Catlin, E A; Ezzell, R M; Donahoe, P K et al. (1993) Identification of a receptor for human mullerian inhibiting substance. Endocrinology 133:3007-13
MacLaughlin, D T; Levin, R K; Catlin, E A et al. (1992) Identification of mullerian inhibiting substance specific binding in human cell lines. Horm Metab Res 24:570-5
Catlin, E A; Ezzell, R M; Donahoe, P K et al. (1992) Mullerian inhibiting substance binding and uptake. Dev Dyn 193:295-9