- 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.
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.
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