Our research focuses on parturition, the process of birth. Specifically we are interested in the molecular events that bring about remodeling of the cervix from a closed rigid structure to one that expands sufficiently to allow passage of a term fetus. A better understanding of this process is required to devise therapies to prevent preterm birth which occurs in 14% of pregnancies in this country. Our studies have focused on the endocrine events that initiate cervical ripening, characterization of proteoglycans and glycosaminoglycans that disrupt the organization of the cervical extracellular matrix during remodeling, and the role of inflammatory cells in this process. These studies are carried out in normal mice and mice with defects in cervical ripening.
Two mouse models with defects in cervical remodeling are studied in our laboratory. The first is a targeted mutant mouse deficient in the enzyme steroid 5-alpha reductase type 1 (Srd5a1). The steroid hormone progesterone is made in large amounts during pregnancy and is required for maintenance of pregnancy. Progesterone function must be inactivated at parturition to allow cervical ripening and initiation of uterine contractions. Srd5a1 is important in metabolism of progesterone to a less active progestin , dihydroprogesterone. Mice deficient in Srd5a1 have elevated progesterone in cervical tissue and fail to initiate normal cervical ripening. A second mouse model is a transgene insertional mutant in which disruption of a gene on mouse chromosome 6 has led to a defect in normal growth of the cervix and a failure of cervical ripening at term. Studies to identify the novel gene responsible for the defect and the etiology of the phenotypes are underway.
In the nonpregnant cervix collagen fibers are aligned and form fibril bundles with great tensile strength. During pregnancy there is a progressive rearrangement of collagen fibers, loss of fiber length, increased spaces between fibrils and increased collagen turnover. These changes in collagen structure that leads to loss of tensile strength are in part regulated by changes in the composition and abundance of proteglycans and glycosaminoglycans (GAG) that associate with collagen. Studies in our laboratory are focused at understanding the changes in small leucine rich proteoglycans and the GAG-hyaluronan in the cervix during cervical softening and ripening. The increase in hyaluronan results from increased expression of the enzyme hyaluronan synthase 2. The regulation of hyaluronan synthase 2 during pregnancy and parturition is one research focus in the laboratory along with studies to define the physiological roles of the small proteoglycans and hyaluronan.
One histological feature of normal cervical ripening in numerous species is the infiltration of leukocytes into cervical stroma. The release of proteases by leukocytes is purported to facilitate degradation of the cervical extracellular matrix during ripening. While there is evidence of inflammatory cells in infection induced preterm labor, an unequivocal role for invading leukocytes in initiation of normal cervical ripening remains controversial due to timing of tissue collection and variability of biopsy site in human studies. Our studies in the mouse are directed at defining the timing of inflammatory cell migration and activation relative to cervical ripening.
RESEARCH INTERESTS
Parturition (the process of labor)
Cervical Ripening
Reproductive Biology (male and female)
RECENT PUBLICATIONS
Straach, KJ, Shelton, JM, Richardson, JA, Hascall, VC, Mahendroo, MS, "Regulation of hyaluronan expression during cervical ripening" Glycobiology, 15:55-65, 2005
Word RA, Landrum, CP, Timmons, BC, Mahendroo, MS, "Transgene insertion results in defective parturition: insights from a new model" Biology of Reproduction, 73:1046-56, 2005
Timmons, BC and Mahendroo, MS, "Timing of neutrophil activation and expression of proinflammatory markers do not support a role of neutrophils in cervical ripening in the mouse" Biology of Reproduction, 74:236-45, 2006
Timmons, BC, Mitchell, S, Gilpin, C, Mahendroo, MS, "Dynamic changes in the cervical epithelial tight junction complex and differentiation occur during cervical ripening and parturition" Endocrinology, 148:1278-1287, 2007
Read, CP, Word RA, Ruscheinsky, M, Timmons, BC, Mahendroo, MS, "Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase" Reproduction, 134:327-340, 2007
SIGNIFICANT PUBLICATIONS
Mahendroo MS, Cala KM, Russell DW, "5alpha-reduced androgens play a key role in murine parturition." Molecular Endocrinology, 10:380-392, 1996
Mahendroo MS, Cala KM, Landrum CP, Russell DW, "Fetal death in mice lacking 5alpha-reductase type 1 caused by estrogen excess." Molecular Endocrinology, 11:917-927, 1997
Mahendroo MS, Porter A, Russell DW, Word RA, "The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening." Molecular Endocrinology, 13:981-992, 1999
Mahendroo MS, Cala KM, Hess DL, Russell DW, "Unexpected virilization in male mice lacking steroid 5α-reductase enzymes" Endocrinology, 142:4652-4662, 2001
Mahendroo M, Wilson JD, Richardson JA, Auchus RJ, "Steroid 5α-reductase isozyme 1 promotes formation of 5α-androstane-3α,17β-diol in the leydig cell of immature mouse testis by two pathways" Mol Cell Endocrinology, 222:113-120, 2004
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