REGULATION OF MYOMETRIAL CYCLASE ISOTYPE EXPRESSION

子宫肌环化酶同种型表达的调节

基本信息

批准号：
2657552
负责人：
KAREN S LINDEMAN
金额：
$ 10万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 1998-06-30
项目状态：
已结题

项目摘要

Mechanisms underlying normal changes in uterine tone are not well understood. Pathological situations of increased uterine tone lead to conditions such as preterm labor and uterine hypertonus during labor analgesia. A proposed mechanism of uterine hypertonus involves acute decreases in catecholamine levels, but the relevant myometrial signal transducing pathways have not been fully elucidated. The most important pathways producing uterine contraction and relaxation are the oxytocin (OT) and the beta adrenergic receptor (betaAR)-mediated pathways. Our goal is to understand crossregulation between these two pathways in nonpregnant myometrium, how pregnancy affects crossregulation, and how crossregulation affects responses to changes in betaAR activity. Preliminary results show that chronic OT pretreatment inhibits basal and stimulated adenylyl cyclase (AC) activity in vivo and in vitro. We hypothesize that OT-induced dysfunction of the stimulatory AG pathway, at the level of AC, leads to uterine hypertonus as betaAR input is withdrawn. We will study cultured pregnant and nonpregnant rat and human myometrial cells pretreated with OT. To identify the mechanism of crossregulation, we will measure numbers and affinities of betaAR and OT receptors, and AC activity. To identify the role of specific isoforms of AC, we will determine presence and quantities of mRNA for those isoforms involved in the down-regulation of AG. To further develop a model of in vivo responses, we will characterize cultured cells from nonpregnant and pregnant rats and human subjects. Knowledge of crossregulation as a common mechanism of uterine hyperactivity will lead to prevention of fetal distress and preterm labor, thus reducing the number of unnecessary cesarean sections. This will result in improved care of both the mother and child and to decreased costs of childbirth and prematurity.

子宫音调正常变化的基础机制不好理解。子宫张力增加的病理状况导致劳动期间早产和子宫催眠等疾病镇痛。提议的子宫催眠机制涉及急性儿茶酚胺水平降低，但相关的肌层信号转导途径尚未完全阐明。最多产生子宫收缩和放松的重要途径是催产素（OT）和β肾上腺素能受体（betaar）介导的途径。我们的目标是了解这两个之间的交叉调节非怀孕肌层中的途径，怀孕如何影响交叉调节以及交叉调节如何影响对变化的反应在Betaar活动中。初步结果表明慢性OT 预处理抑制基础并刺激腺苷酸环化酶（AC）体内和体外活性。我们假设OT引起的 AC水平的刺激AG途径的功能障碍导致由于贝塔尔输入而撤回子宫高血压。我们将学习培养的孕妇和非怀孕大鼠和人肌层细胞用OT预处理。为了确定交叉调节的机制，我们将测量βAR和OT受体的数量和亲和力，以及AC 活动。为了确定特定的AC的特定同工型的作用，我们将确定涉及的同工型的存在和数量在AG的下调中。进一步开发体内模型响应，我们将表征来自非怀孕和的培养细胞怀孕的大鼠和人类受试者。对交叉调节的了解子宫多动症的常见机制将导致预防胎儿苦恼和早产，从而减少了数量不必要的剖宫产。这将改善护理母亲和儿童都降低了分娩的成本和早熟。