BIOMECHANICAL-BIOCHEMICAL-MOLECULAR EVENTS IN GESTATIONAL CERVICAL REMODELING

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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