BIOMECHANICAL-BIOCHEMICAL-MOLECULAR EVENTS IN GESTATIONAL CERVICAL REMODELING

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 早产仍然是可预防的围产期发病率和死亡率的主要原因。尽管使用了许多能有效抑制子宫活动的药物，但早产率在过去20年中并未下降。目前还没有有效的治疗方法来预防宫颈扩张，宫颈扩张在特发性早产中似乎同样重要，甚至可能更重要。极早早产长期以来一直被认为是一个问题，由于宫颈功能障碍。我们建议使用机械工程和分子生物学之间的结合方法来确定在怀孕期间决定宫颈结构完整性的分子、生物化学和结构特征。该建议还调查了雄激素在调节宫颈功能中的作用，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，胶原蛋白和蛋白聚糖。子宫颈在怀孕的后半段开始变弱，此时子宫正在扩张，导致压力增加。过早的颈椎短缩表明胶原和蛋白多糖重塑不能适应压力的增加。我们招募建立和新的技术来表征宫颈内的糖胺聚糖和核心蛋白质组成，以实现三个特定的目标。1）确定子宫颈的生化和结构变化，这些变化有助于妊娠后半期子宫颈生物力学特性的变化。2）表征由雄激素和孕酮拮抗剂诱导的子宫颈中的生化和结构变化，从而导致生物力学性质的变化。该提案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中的这些特定目标。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机械特性。我们的长期目标是开发新的治疗方法，以防止非常早期的早产，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.