Cervical Ripening and Histone Acetylation

 描述（由申请人提供）：几十年来，已知甘草素在分娩前的宫颈成熟中发挥重要作用。然而，其诱导宫颈成熟的机制在很大程度上是未知的。在R21的应用中，我们发现组蛋白去乙酰化酶（HDAC）抑制剂逆转了PGE 2介导的15-羟基前列腺素脱氢酶（15-PGDH）下调以及考克斯-2和IL-8表达的诱导。随着这一发现，研究这些抑制剂是否能阻断宫颈过早成熟具有及时和临床意义。以前的研究表明，HDAC抑制剂延迟小鼠的生理分娩，对母体或胎儿没有不良影响。在本申请中，我们建议（i）确定HDAC抑制剂逆转PGE 2介导的对宫颈考克斯-2和IL-8的作用的机制，以及（ii）使用临床前动物模型来研究HDAC抑制剂对早产宫颈重塑和体内分娩的作用。

 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.