Cervical Ripening and Histone Acetylation

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 DESCRIPTION (provided by applicant): For decades, prostaglandins have been known to play an important role in cervical ripening prior to labor. The mechanisms of prostaglandin-induced cervical ripening, however, are largely unknown. In this R21 application, we show that histone deacetylase (HDAC) inhibitors reverse PGE2-mediated downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and induction of COX-2 and IL-8 expression. With this discovery, it is timely and clinically significant to investigate if these inhibitors canblock premature cervical ripening. Previous investigations have shown that HDAC inhibitors delay physiological labor in mice with no adverse maternal or fetal effects. In this application, we propose to (i) determine the mechanisms by which HDAC inhibitors reverse PGE2-mediated effects on cervical COX-2 and IL-8, and (ii) use a preclinical animal model to study the effect of HDAC inhibitors on preterm cervical remodeling and labor in vivo.