SIGNALING AND UTERINE CONTRACTILITY DURING PREGNANCY

描述（由申请人提供）：早产发生率高达10%，占新生儿死亡的75%。迫切需要对正常妊娠期间收缩性静止的机制有更深入的了解。本提案的总体目的是验证基础细丝（肌动蛋白）和粗丝（肌球蛋白）调节机制在正常和异常妊娠和分娩期间长期改变的假设。具体目的是：(1)探讨肌动蛋白结合蛋白Caldesmon （CaD）蛋白水平或磷酸化水平的变化对定时妊娠大鼠模型和人体组织样本中妊娠依赖性收缩性变化的影响；(2)研究细胞外调节激酶（ERK1/2）信号通路改变导致以下变化的假设：(a) CaD活性；和/或(b)大鼠和人妊娠和分娩时子宫肌层收缩力的变化；(3)探讨肌球蛋白磷酸酶的调节参与大鼠和人妊娠依赖性收缩性变化的假说；(4)研究导致妊娠依赖性收缩性变化的信号转导协调至少部分是由支架蛋白（caveolin）介导的。由于人体组织的供应有限，将使用定时大鼠模型来详细绘制信号通路和计划的体内药物研究。然而，人类样本将同时收集，并在较长的时间基础上，将用于测试从大鼠组织获得的关键结果。将采用多学科方法，结合收缩功能评估、生化测量、定量共聚焦显微镜、器官培养、反义实验和体内药物治疗来检验上述假设。我们希望，如果新的机制可以被识别和定义，所涉及的途径将代表新的潜在目标，为治疗干预的情况下，早产和功能障碍的劳动。

DESCRIPTION (provided by applicant): Preterm delivery occurs in up to 10% of births and accounts for 75% of neonatal deaths. A greater understanding of the mechanisms of contractile quiescence during normal pregnancy is sorely needed. The general aim of this proposal is to test the hypothesis that basal thin (actin) and thick (myosin) filament regulatory mechanisms are chronically altered during normal and abnormal pregnancy and labor. The specific aims are: (1) To investigate the hypothesis that changes in either the protein levels or phosphorylation levels of the actin binding protein, Caldesmon (CaD) contribute to gestation dependent contractility changes in both a timed pregnant rat model and in human tissue samples; (2) To investigate the hypothesis that changes in Extracellular Regulated Kinase (ERK1/2) signaling contribute to changes: (a) in CaD activity; and/or (b) in the contractility of myometrium during pregnancy and labor in the rat and human; (3) To investigate the hypothesis that regulation of Myosin Phosphatase is involved in gestation-dependent changes in contractility in the rat and human; and (4) To investigate the hypothesis that coordination of signal transduction that leads to gestation-dependent changes in contractility is, at least in part, mediated by the action of the scaffolding protein, caveolin. Because of the limited supply of human tissue, a timed rat model will be used for the detailed mapping of signaling pathways and the planned in vivo drug studies. However, human samples will be collected in parallel and, on a longer time base, will be used to test critical results obtained with the rat tissue. A multidisciplinary approach will be used, combining functional assessment of contractility, biochemical measurements, quantitative confocal microscopy, organ culture, antisense experiments, and in vivo drug treatment to test the above hypotheses. It is hoped that if novel mechanisms can be identified and defined, the pathways involved will represent new potential targets for therapeutic intervention in cases of preterm and dysfunctional labor.