- Mahendroo Preterm birth (PTB) affects 15 million children world-wide annually contributing significantly to infant mortality and the potential for lifelong health complications in survivors. An incomplete understanding of risk factors that lead to preterm birth has limited development of tools for early, accurate assessment of PTB risk as well as therapies for prevention. Our recent studies have highlighted the important role that the cervical epithelia play in providing barrier and immune protection during pregnancy and led to the identification of ?cervical epithelial dysfunction? as a new risk factor for preterm birth. Through pregnancy and parturition, the epithelia must proliferate, differentiate, and form a junctional and mucosal barrier to protect the reproductive tract from ascending infection and resulting risk of preterm birth. During pregnancy these epithelial responsibilities are regulated in part by extracellular matrix cues, specifically by the increased synthesis of the glycosaminoglycan hyaluronan (HA). Mice lacking HA synthesis in the cervix display abnormal epithelial differentiation, increased epithelial and mucosal permeability and increased PTB rates in response to ascending infection. The increase in cervical hyaluronan during late pregnancy is regulated by increased hyaluronan synthase 2 (Has2) gene expression. The focus of this study is thus to understand i) the mechanism by which HA participates in cervical epithelial competency, ii) identify downstream transcriptome targets of HA and iii) understand the transcriptional regulation of Has2 expression in the cervix. We will test the overall hypothesis that HA?s ability to maintain epithelial cervical barrier function and immune-protection requires interactions with HA-interacting proteins and mediates processes involved in epithelial differentiation, barrier function and response to toll-like receptor signaling.

Public Health Relevance

Understanding the molecular processes that modulate premature cervical remodeling is critical to the identification of therapeutic targets and the development of improved tools for early risk detection of preterm birth. Our recent studies focused on the molecule hyaluronon, elucidated for the first time, that disruption of the cervico-vaginal epithelial barrier leads to increased sensitivity to infection-induced preterm birth. The focus of this application is to utilize genomic, cell biology and biochemical approaches to understand how hyaluronan functions to create a protective mucosal and epithelial barrier to help fight ascending infections that lead to preterm birth.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
United States
Zip Code
Mahendroo, Mala (2018) Cervical hyaluronan biology in pregnancy, parturition and preterm birth. Matrix Biol :
Mogami, Haruta; Kishore, Annavarapu Hari; Word, R Ann (2018) Collagen Type 1 Accelerates Healing of Ruptured Fetal Membranes. Sci Rep 8:696
Itoh, Hiroko; Mogami, Haruta; Bou Nemer, Laurice et al. (2018) Endometrial stromal cell attachment and matrix homeostasis in abdominal wall endometriomas. Hum Reprod 33:280-291
Willcockson, Alexandra R; Nandu, Tulip; Liu, Cheuk-Lun et al. (2018) Transcriptome signature identifies distinct cervical pathways induced in lipopolysaccharide-mediated preterm birth. Biol Reprod 98:408-421
Manders, Dustin B; Kishore, Hari Annavarapu; Gazdar, Adi F et al. (2018) Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer. Oncotarget 9:14251-14267
Babayev, Samir N; Kanchwala, Mohammed; Xing, Chao et al. (2018) Thrombin Alters Human Endometrial Stromal Cell Differentiation During Decidualization. Reprod Sci :1933719118768705
Mendelson, Carole R; Montalbano, Alina P; Gao, Lu (2017) Fetal-to-maternal signaling in the timing of birth. J Steroid Biochem Mol Biol 170:19-27
Kishore, Annavarapu Hari; Liang, Hanquan; Kanchwala, Mohammed et al. (2017) Prostaglandin dehydrogenase is a target for successful induction of cervical ripening. Proc Natl Acad Sci U S A 114:E6427-E6436
Babayev, Samir N; Park, Chan Woo; Keller, Patrick W et al. (2017) Androgens Upregulate Endometrial Epithelial Progesterone Receptor Expression: Potential Implications for Endometriosis. Reprod Sci 24:1454-1461
Chen, Chien-Cheng; Montalbano, Alina P; Hussain, Imran et al. (2017) The transcriptional repressor GATAD2B mediates progesterone receptor suppression of myometrial contractile gene expression. J Biol Chem 292:12560-12576

Showing the most recent 10 out of 12 publications