BIOMECHANICAL-BIOCHEMICAL-MOLECULAR EVENTS IN GESTATIONAL CERVICAL REMODELING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 早产仍然是导致可预防的围产期发病率和死亡率的主要因素。尽管使用了许多可以有效抑制子宫活动的药物，但在过去的20年里，早产率并没有下降。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，而且可能更重要。由于宫颈功能障碍，极早早产一直被认为是一个问题。我们建议使用机械工程和分子生物学相结合的方法来确定决定怀孕期间宫颈结构完整性的分子、生化和结构特征。这项建议还调查了雄激素在调节颈椎功能中的作用，这是一项新颖的研究，并得到了临床和间接实验观察的支持。两个主要的细胞外成分为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，当子宫扩张时，宫颈开始变弱，造成更大的压力。宫颈过早缩短表明胶原蛋白和蛋白多糖重塑失败，无法适应压力的增加。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成分，以实现三个特定的目标。1)确定在妊娠后半期子宫颈的生化和结构变化对其生物力学特性的影响。2)研究雄激素和孕激素拮抗剂引起的宫颈生化和结构改变，从而导致生物力学特性的改变。这项提案的具体目标将为防治早产以及与这一问题相关的发病率和死亡率提供新的治疗目标。我们使用体内和体外两种方法在大鼠身上解决这些特定的目标。虽然我们正在调查颈椎的功能，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来预防早产，早产是一种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.