In our laboratory, we utilize molecular and cellular approaches to decipher mechanisms of extracellular matrix remodeling of the female reproductive tract in both physiologic states (e.g., during pregnancy, parturition, and the puerperium) and pathologic conditions (pelvic organ prolapse, urinary incontinence, and injury of the external anal sphincter).
Using cultured primary human cervical stromal cells, genetically-altered mice, and tissue samples from the human cervix and vagina, our lab examines the balance between matrix synthesis and degradation during cervical ripening and the development of pelvic organ prolapse.
Our research focuses on three specific areas: cervical ripening, pelvic floor and vaginal wall, and the role of aging and mesenchymal stem cells in recovery of the pelvic floor from injury.
The overall goal of our research program involving the cervix is to understand the transcriptional regulation of genes that function to resist effacement and dilation of the cervix caused by the gravitational effects of the growing fetus and placenta during pregnancy. We suggest that activation of signal transduction events leading to cervical ripening are opposed by transcriptional programs to maintain cervical integrity during gestation. We identified and cloned a novel isoform of the transcription factor microphthalmia-associated transcription factor (MiTF) as one of the important transcriptional regulators of cervical competency during pregnancy.
MiTF is a basic helix-loop-helix leucine zipper transcription factor that plays a crucial role in the differentiation of certain cell-specific lineages. This cell-specific isoform is highly expressed in the pregnant cervix prior to labor but is dramatically downregulated in cervical stromal cells from women in labor. Our aims are (i) to determine tissue- and isoform-specific expression of MiTF in cervix and myometrium during pregnancy and postpartum, (ii) to identify target genes of MiTF regulation in cervical stromal cells, (iii) to identify positive and negative regulators of MiTF gene expression in stromal and smooth muscle cells in the uterus and cervix, and (iv) to understand the mechanisms that lead to MiTF degradation during cervical ripening. The roles of extracellular biosynthetic enzymes including lysyl oxidases, and proteolytic processing enzymes such as procollagen N- and C-proteinases are of particular interest in cervical ripening. Thus, we analyze the in vitro and in vivo regulation of these enzymes, of other extracellular matrix components, and of selected cytokines during pregnancy, cervical ripening, and dilation. We are also interested in the mechanisms by which the nuclear hormone receptors for estrogen and progesterone orchestrate matrix remodeling of the cervix.
The pelvic floor is a complex dynamic system that supports the vagina and pelvic viscera. In women, failure of pelvic organ support is common. A wealth of literature has established that vaginal parity and aging are important risk factors for pelvic organ prolapse in women. The specific mechanisms by which vaginal delivery and aging lead to failure of pelvic organ support are unknown. For decades, pelvic surgeons have recognized that women with prolapse often exhibit abnormal connective tissues in the pelvic floor. We seek to define the cellular and molecular mechanisms that confer abnormal structural and functional support to the pelvic organs. By definition, remodeling of connective tissue involves both synthesis and degradation of the extracellular matrix. Remodeling of connective tissue of the pelvic floor in pelvic organ prolapse likely represents aberrations in both synthesis and degradation of matrix components. Our investigations, together with the phenotype of LOXL1, Fbln-3, and Fbln-5 knockout mice, have led to the idea that pelvic organ prolapse, at least in some women, may represent an elastinopathy brought about by different conditions including aging and incomplete remodeling of the vaginal wall after parturition. Disturbances in the balance between synthesis/assembly and degradation of matrix components of connective tissues of the pelvic floor may result in slow, but progressive, loss of pelvic organ support. Thus, our research interests in this area center on the role of certain proteases (including MMP-9), two novel serine proteases, and defective elastogenesis in the pathogenesis of pelvic organ prolapse.
The Role of Aging and Mesenchymal Stem Cells in Recovery of the Pelvic Floor from Injury, Aging, and Recovery
Our lab is in collaboration with Clifford Wai, M.D., to understand the role of aging and stem cells in recovery of the lower urinary tract and external anal sphincter from birth trauma. We seek to understand the mechanisms of injury and healing and how these processes are affected by age, hypoxia, and stem cells.