BIOMECHANICAL-BIOCHEMICAL-MOLECULAR EVENTS IN GESTATIONAL CERVICAL REMODELING

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。早产仍然是导致可预防的围产期发病率和死亡率的主要原因。尽管使用了许多药物，可以有效地抑制子宫活动，早产率没有下降，在过去的20年。目前还没有有效的治疗方法来预防宫颈扩张，而宫颈扩张在特发性早产中似乎同样重要，甚至可能更重要。极早早产一直被认为是由宫颈功能障碍引起的问题。我们建议采用机械工程和分子生物学相结合的方法来确定决定妊娠期间子宫颈结构完整性的分子、生化和结构特征。本研究还探讨了雄激素在宫颈功能调节中的作用，这是新颖的，并得到了临床和间接实验观察的支持。两种主要的细胞外成分为子宫颈提供结构完整性，胶原蛋白和蛋白多糖。在怀孕的后半段，当子宫扩张导致压力增加时，子宫颈开始变弱。颈椎过早缩短表明胶原蛋白和蛋白聚糖重塑不能适应压力的增加。我们利用现有的和新的技术来表征宫颈内的糖胺聚糖和核心蛋白质组成，以达到三个特定的目的。1)确定妊娠后半期子宫颈生物力学特性变化的生化和结构变化。2)探讨雄激素和黄体酮拮抗剂诱导子宫颈生化和结构变化导致的生物力学特性变化。该建议的具体目标将为防治早产以及与此问题相关的发病率和死亡率提供新的治疗靶点。我们使用体内和体外方法来解决大鼠的这些特定目标。虽然我们正在研究颈椎功能，但我们的发现应该有助于了解其他软组织和器官的力学特性。我们的长期目标是开发新的治疗方法，以预防极早早产，这是一个主要的经济和健康负担

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Premature birth remains the leading contributor to preventable perinatal morbidity and mortality. Despite the use of numerous agents that can effectively suppress uterine activity prematurity rates have not declined over the past 20 years. No effective therapies have been developed to prevent cervical dilation, which appears to be as important and possibly more important in idiopathic preterm labor. Extremely early preterm birth has long been thought to be a problem due to cervical dysfunction. We proposed to determine the molecular, biochemical and structural characteristics that determine the structural integrity of the cervix during pregnancy using a combined approach between mechanical engineering and molecular biology. This proposal also investigates the role of androgens in the regulation of cervical function, which is both novel and supported by clinical and indirect experimental observations. Two main extracellular components provide structural integrity to the cervix, collagen and proteoglycans. The cervix begins to weaken during the second half of pregnancy when the uterus is expanding causing increased stress. Premature cervical shortening indicates a failure in collagen and proteoglycan remodeling to accommodate the increase in stress. We enlist established and new techniques to characterize the glycosaminoglycan and the core protein composition within the cervix to achieve three specific aims. 1)To determine the biochemical and structural changes in the cervix that contributes to changes in its biomechanical properties during the second half of gestation. 2)To characterize the biochemical and structural changes in the cervix induced by androgens and progesterone antagonists leading to changes in biomechanical properties. The specific aims of this proposal will provide new therapeutic targets in the fight against preterm birth and the morbidity and mortality associated with this problem. We use both in-vivo and in-vitro approaches to address these specific aims in the rat. Although we are investigating cervical function our findings should provide understanding into mechanical characteristics of other soft tissues and organs. Our long term objectives are to develop new therapies to prevent very early preterm birth which is a major economic and health burden