Project 3 REGULATION AND FUNCTION OF HYALURONAN

在所有哺乳动物物种中，成功分娩需要子宫收缩的及时开始和子宫颈的重塑，以允许胎儿通过产道。控制这些相互交织的过程的分子机制仍然知之甚少。每年，全世界约有450万严重早产儿因无法正常分娩而出生，与过期妊娠分娩有关的并发症给母亲和儿童造成无数问题。拟议的研究旨在进一步了解促进宫颈软化和成熟的分子过程。在正常小鼠和宫颈成熟缺陷小鼠中的研究已经揭示了透明质酸合酶2在糖胺聚糖透明质酸（HA）的产生中的重要作用。我们假设HA在成熟过程中具有多种作用。第一个作用是结构作用，其中HA提供水合的松散缔合基质，以允许基质的适当重构。我们提出HA的第二个作用是在成熟过程中启动正常炎症反应所需的细胞信号传导事件。将进行体内和体外研究以了解透明质酸合酶2在宫颈成熟中的调节。将启动旨在评价HA生理功能的研究。这包括鉴定宫颈中对HA功能至关重要的HA结合蛋白，评估HA分子量的变化和HA细胞表面受体CD44的表征。最后，我们将确定HA含量的异常升高或降低是否在与宫颈机能不全、先兆早产或引产后未能进展的过期妊娠妇女相关的并发症中起作用。这些研究中应用的综合方法与本提案中的其他项目相结合，将为控制小鼠和女性分娩的机制提供新的分子见解，并将建立一个框架，以设计预防分娩相关并发症的治疗方法。

Successful parturition in all mammalian species requires a timely onset of uterine contractions and remodeling of the cervix to allow passage of the fetus through the birth canal. The molecular mechanisms controlling these intertwined processes remain poorly understood. Each year, some 4.5 million severely premature infants are born worldwide due to failure of normal parturition, and complications associated with delivery in post term pregnancies cause innumerable problems in both mother and child. The proposed studies are designed to further our understanding of the molecular processes that facilitate cervical softening and ripening. Studies in normal mice and mice with defects in cervical ripening have revealed an important role of the enzyme hyaluronan synthase 2 in production of the glycosaminoglycan hyaluronan (HA). We hypothesize HA has multiple roles in the ripening process. The first role is a structural one in which HA provides a hydrated loosely associated matdx to allow appropriate restructuring of the matrix. A second role of HA we propose, is in initiation of cell signaling events required for a normal inflammatory response during the ripening process. In vivo and in vitro studies will be carried out to understand regulation of hyaluronan synthase 2 in cervical ripening. Studies designed to evaluate the physiological functions of HA will be initiated. This includes identification of HA-binding proteins in the cervix that are critical to HA function, evaluation of changes in HA molecular weight and characterization of the HA cell surface receptor, CD44. Finally, we will determine if abnormally elevated or reduced HA content plays a role in complications associated with cervical incompetence, threatened preterm labor, or in women with postterm pregnancies who fail to progress after induction of labor. The integrated approaches applied in these studies in combination with the other projects in this proposal will provide novel molecular insight into the mechanisms controlling parturition in mice and women and will establish a framework from which to devise therapies to prevent complications associated with parturition.