SIGNALING AND UTERINE CONTRACTILITY DURING PREGNANCY

描述（由申请人提供）：早产发生在高达10%的出生，占新生儿死亡的75%。我们迫切需要更深入地了解正常妊娠期子宫收缩静止的机制。这项建议的总体目的是测试的假设，即基础薄（肌动蛋白）和厚（肌球蛋白）丝的调节机制，在正常和异常妊娠和分娩过程中慢性改变。具体目标是：（1）研究肌动蛋白结合蛋白Caldesmon（CaD）的蛋白质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力变化的影响的假设;（2）研究细胞外调节激酶（ERK 1/2）信号转导的变化对CaD活性变化的影响的假设;和/或（B）在大鼠和人的妊娠和分娩期间子宫肌层的收缩性;（3）研究肌球蛋白磷酸酶的调节涉及大鼠和人的收缩性的妊娠依赖性变化的假设;和（4）研究导致收缩性的妊娠依赖性变化的信号转导的协调，至少部分地，由支架蛋白小窝蛋白的作用介导。由于人体组织的供应有限，定时大鼠模型将用于信号通路的详细映射和计划的体内药物研究。 然而，将平行采集人体样本，并在较长的时间基础上用于检测大鼠组织获得的关键结果。将使用多学科方法，结合收缩力的功能评估、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测试上述假设。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的治疗干预早产和功能障碍的情况下。

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.