It is our goal to define the genetic and epigenetic mechanisms that mediate expression of specific genes in a tissue- and cell-specific manner, that activate gene expression at distinct phases of embryonic development, and modulate their expression by hormones and second messengers. To accomplish these goals, we are studying the regulation of two genes of great physiological relevance: (1) the gene encoding the major protein in lung surfactant, surfactant protein-A (SP-A), a C-type lectin that plays a role in host defense within the lung alveolus, and; (2) the CYP19 gene, which encodes aromatase, the critical enzyme in estrogen biosynthesis.
The SP-A gene is expressed specifically in lung type II cells. The type II cell is unique in its ability to synthesize surfactant, a developmentally-regulated, phospholipid-rich lipoprotein that reduces surface tension within the lung alveolus and is essential for normal breathing. SP-A gene expression is developmentally-regulated in fetal lung in concert with type II cell differentiation and augmented synthesis of surfactant phospholipids. SP-A gene expression in cultured fetal lung type II cells is upregulated by proinflammatory cytokines (e.g. interleukin-1) and by hormones that increase cyclic AMP, and is inhibited by glucocorticoids. Cyclic AMP and IL-1 stimulation of SP-A expression is dependent upon a critical O2 tension. Studies using transgenic mice and primary cultures of type II pneumocytes have been implemented to map the genomic elements that mediate the tissue-/cell-specific, developmental and hormonal regulation of SP-A expression. Transcription factors and coregulators that bind to these genomic regions have been characterized and the mechanisms that regulate their expression, DNA-binding and activation are being defined. Recent studies are focused on the epigenetic mechanisms that mediate developmental, hormonal and O2 regulation of SP-A gene expression in fetal lung.
The human CYP19 gene is selectively expressed in a number of tissues, including ovarian granulosa and luteal cells, adipose stromal cells, syncytiotrophoblast of the placenta, and discrete regions of the brain. Aromatase expression in these tissues is regulated by the use of different tissue-specific promoters, which lie upstream of unique first exons encoding the 5?-untranslated regions of the aromatase mRNAs. Transgenic mice and transfected cells have been used to define the genomic regions, response elements and transcription factors that mediate tissue/cell-specific and hormonal regulation of the human CYP19 gene in placenta, ovary and brain. Recent studies are focused on the cellular and molecular mechanisms for aromatase upregulation in pathologic states, including endometriosis and breast cancer.
We recently initiated a research program to define the mechanisms for the initiation of labor - both at term and at preterm. The central hypothesis is that the initiation of spontaneous labor in humans, as well as other mammalian species, is associated with an inflammatory response that results in increased prostaglandin synthesis and promotes a concerted series of biochemical and molecular events that negatively impacts the ability of the progesterone receptor (PR) to maintain myometrial quiescence. We have obtained evidence that PR function near term may be compromised by changes at several levels, including: (1) increased expression of inhibitory PR isoforms; (2) increased local metabolism of progesterone to inactive products within the uterus and cervix, and; (3) altered expression of coactivators and/or corepressors that result in decreased PR transcriptional activity. We recently made the intriguing observation that upregulation of inflammatory response pathways leading to labor is triggered by augmented secretion of SP-A by the maturing fetal lung into amniotic fluid. The secreted SP-A acts on fetal macrophages, which migrate to the maternal uterus where they release cytokines, resulting in activation of NF-kB, a transcription factor that promotes inflammatory signaling pathways and antagonizes PR function. Studies are ongoing to characterize fetal macrophages during late gestation, the mechanisms leading to their activation and their paths of migration to the uterus.
RESEARCH INTERESTS
Molecular Mechanisms in the developmental, hormonal and tissue-specific regulation of surfactant protein gene expression in fetal lung tissue
Molecular mechanisms in the regulation of aromatase in estrogen-producing cells
Mechanisms in the initiation of parturition
RECENT PUBLICATIONS
Hardy DB, Janowski BA, Corey DR, Mendelson CR, "Progesterone receptor plays a major antiinflammatory role in human myometrial cells by antagonism of nuclear factor-kappaB activation of cyclooxygenase 2 expression" Mol Endocrinol, 20:2724-2733, Fall 2006
Islam KN, Mendelson CR, "Glucocorticoid/glucocorticoid receptor inhibition of surfactant protein-A (SP-A) gene expression in lung type II cells is mediated by repressive changes in histone modification at the SP-A promoter" Mol Endocrinol, 22:585-596, Spring 2008
Bukulmez O, Hardy DB, Carr BR, Word RA, Mendelson CR, "Inflammatory status influences aromatase and steroid receptor expression in endometriosis" Endocrinology, 149:1190-1204, Spring 2008
Islam KN, Mendelson CR., "Permissive effects of oxygen on cyclic AMP and interleukin-1 stimulation of surfactant protein A gene expression are mediated by epigenetic mechanisms" Mol Cell Biol, 26:2901-2912, Spring 2006
Liu D, Hinshelwood MM, Giguere V, Mendelson CR, "Estrogen related receptor-alpha enhances surfactant protein-A gene expression in fetal lung type II cells" Endocrinology, 147:5187-5195, Fall 2006
SIGNIFICANT PUBLICATIONS
Evans, C.T., Ledesma, D.B., Schulz, T.Z., Simpson, E.R., and Mendelson, C.R., "Isolation and characterization of a complementary DNA specific for human aromatase cytochrome P-450 mRNA" Proc. Natl. Acad. Sci. USA, 83:6387-6391, 1986
Kamat, A., Graves, K.H., Smith, M.E., Richardson, J.A., and Mendelson, C.R., "A 500 bp region, ~40 kb upstream of the human CYP19 (aromatase) gene mediates placenta-specific expression in transgenic mice" Proc. Natl. Acad. Sci. USA, 96:4575-4580, 1999
Alcorn. J.A., Hammer, R.E., Graves, K.H., Smith M.E., Maika, S.D., Michael, L.F., Gao, E., Wang, Y., and Mendelson, C.R., "Identification of regulatory regions involved in lung cell-specific, developmental, and hormonal regulation of expression of the rabbit surfactant protein-A (SP A) gene in transgenic mice" Amer. J. Physiol.: Lung Cell. Mol. Physiol., 277:L349-L361, 1999
Islam, K., and Mendelson, C.R., "Potential role of nuclear factor kappa B and reactive oxygen species (ROS) in cyclic AMP and cytokine regulation of surfactant protein-A gene expression in lung type II cells" Mol. Endocrinol., 16:1428-1440, 2002
Condon JC, Jeyasuria P, Faust JM and Mendelson CR, "Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of labor" Proc Natl Acad Sci USA, 101:4978-4983, Spring 2004
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