Request for Funding
Medical Student Research Fellowship for Summer 2004
Mentor: Carole R. Mendelson, Ph.D.
Department: Biochemistry
Room number: K3.106
Mail Code: 9038
Phone number: 214-648-2944
E-mail: cmende@biochem.swmed.edu
Project title: Mechanisms in the Initiation of Labor
Human subjects IRB approved project number (where applicable): 1076 02000
Animal subjects IRB approved project number (where applicable): 0057-01-03-3
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Basic
Brief Description of Project:
Approximately 450,000 babies are born prematurely in the U.S. each year. Consequences
of preterm birth range from death and/or lifelong impairment to chronic lung
disease. Despite extensive research, surprisingly little is known regarding
the molecular mechanisms that lead to the initiation of term or preterm labor.
For the first 95% of gestation, the uterus is kept in a quiescent state by progesterone,
which regulates expression of genes that maintain uterine quiescence. While
in most mammals, a drop in serum progesterone levels precedes the onset of labor,
in humans, other primates and guinea pigs, circulating progesterone and uterine
progesterone receptor (PR) levels remain high through term. We postulate that
the initiation of spontaneous labor in humans, as well as other mammalian species,
is caused by a complex and concerted series of biochemical and molecular events
that negatively impact the ability of the PR to regulate target genes in the
uterus that maintain myometrial quiescence. We have recently obtained evidence
that PR function near term may be compromised by: (1) a decline in expression
of certain coactivators that decrease PR transcriptional activity; (2) a decline
in local concentrations of progesterone within the myometrium caused by increased
expression of progesterone metabolizing enzymes, and; (3) an induction of inflammatory
response pathways leading to activation of NF- B, a transcription factor that
antagonizes PR function. We also have obtained intriguing evidence that induction
of inflammatory response pathways leading to inactivation of PR function and
the initiation of labor is caused by augmented secretion of surfactant protein
into amniotic fluid by the maturing fetal lung. Summer research will involve
some aspect of this research.
Previous Research Activities or Publications with Medical Students:
Molsberry, R.L., Carr, B.R., Mendelson, C.R., and Simpson, E.R. hCG binding
to human fetal testes as a function of gestational age. J. Clin. Endocrinol.
Metab. 55:791-794, 1982.
Ng, V.L., Herndon, V.L., Mendelson, C.R., and Snyder, J.M. Characterization
of rabbit surfactant associated proteins. Biochim. Biophys. Acta 754:218-226,
1983.
Anderson, C.M., and Mendelson, C.R. Regulation of the synthesis of cholesterol
side chain cleavage cytochrome P-450 and adrenodoxin in rat Leydig cells. Ann.
N.Y. Acad. Sci. 438:259-268, 1984.
Durham, C.R., Zu, H., Masters, B.S.S., Simpson, E.R., and Mendelson, C.R. Regulation
of aromatase in rat granulosa cells: Indication of synthesis of NADPH-cytochrome
P-450 reductase by FSH and dibutyryl cyclic AMP. Mol. Cell. Endocrinol. 40:211-219,
1985.
Anderson, C.M., and Mendelson, C.R. Regulation of steroidogenesis in rat Leydig
cells in culture: Effect of human chorionic gonadotropin and dibutyryl cyclic
AMP on the synthesis of cholesterol side-chain cleavage and adrenodoxin. Arch.
Biochem. Biophys. 238:378-387, 1985.
Lanoux, M.J., Cleland, W.H., Mendelson, C.R., Carr, B.R., and Simpson, E.R.
Factors affecting the conversion of androstenedione to estrogens by human fetal
hepatocytes in monolayer culture. Endocrinology 117:361-368, 1985.
Anderson, C.M., and Mendelson, C.R. Developmental and hormonal regulation of
cholesterol side chain cleavage cytochrome P-450 in the fetal rabbit testis.
Mol. Cell. Endocrinol. 55:121-130, 1988.
Young, P.P., and Mendelson, C.R. A CRE-like element plays an essential role
in cyclic AMP regulation of the human surfactant protein-A2 (SP-A2) gene. Am.
J. Physiol.: Lung Cell. Mol. Physiol., 271:L287-L299, 1996.
Young, P.P., and Mendelson, C.R. A GT box is essential for basal and cyclic
AMP regulation of the human SP A2 gene in alveolar type II cells: Evidence for
the binding of lung nuclear factors distinct from Sp1. Mol. Endocrinol 11:1082-1093,
1997.
Muenster, M.R., Gao E., Wang, L., Smith M.E., Alcorn, J.L., and Mendelson, C.R.
Role of transcription factor BTEB2 in developmental and cyclic AMP regulation
of surfactant protein A (SP A) gene expression. The Endocrine Society Annual
Meeting, 1998, oral presentation and travel grant award.
Mendelson, C.R., Young, P.P, Michael, L.F., Alcorn, J.L., and Gao, E.E. Transcriptional
regulation of the surfactant protein-A gene. Chest, 111:96S-104S, 1997.
Mendelson, C.R., Young, P.P., Michael, L.F., Gao, E., and Alcorn, J.L. The surfactant
protein A gene and its regulation. In: Lung Surfactant: Cellular and Molecular
Processing. (Rooney, S.A., ed.) pp. 47-73, R.G. Landes, Co., 1998.
Mendelson, C.R., Gao, E., Li, J., Young, P.P., Michael, L.F., and Alcorn, J.L.
Regulation of expression of surfactant protein A. Biochim. Biophys. Acta 1408:132-149,
1998.
Mendelson, C.R., Michael, L.F., Young, P.P., Li, J., and Alcorn, J.L. Cyclic
AMP and glucocorticoid regulation of surfactant protein-A gene expression. In:
Endocrinology of the Lung: Development and Surfactant Synthesis (Mendelson,
C.R., ed.), Humana Press, pp. 59-80, 2000.
Condon, J.C., Jeyasuria, P., Faust, J.M., Wilson, J.W., Mendelson, C.R. A decline
in the levels of progesterone receptor coactivators in the pregnant uterus at
term may antagonize progesterone receptor function and contribute to the initiation
of parturition. Proc. Natl. Acad. Sci. USA 100:9518-9523, 2003.
Condon, J.C., Jeyasuria, P., Faust, J.M., Mendelson, C.R. Expression of surfactant
protein by the fetal lung signals the initiation of parturition. Submitted,
2003.
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