UTERINE RELAXING FACTORS: MOLECULAR ASPECTS OF ACTION

子宫松弛因素：作用的分子方面

• 批准号: 6730944
• 负责人: BARBARA M SANBORN
• 金额: $ 8.42万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-05-01 至 2003-08-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730944
• 关键词: G protein; calcium channel; calcium flux; cyclic AMP; gestational age; hormone receptor; hormone regulation /control mechanism; laboratory rat; muscle contraction; muscle relaxing factor; myometrium; oxytocin; phosphatidylinositols; potassium channel; protein kinase A; receptor coupling; relaxin; single cell analysis; uterus; voltage /patch clamp

DESCRIPTION (Adapted from the Investigator's Abstract): The overall objective of this proposal is to understand the molecular mechanisms by which hormones influence uterine smooth muscle contraction and relaxation. Aim 1 will elucidate the contributions of the oxytocin receptor (OTR) intracellular loops to the specificity of interaction and activation of GTP-binding proteins (G-proteins). Receptor chimeras, site-specific receptor mutants, and the ability of over expressed intracellular loop peptides to inhibit coupling will be used to examine OTR/G-protein interactions. Aim 2 will define the mechanisms by which cAMP inhibits G-protein stimulated phosphatidylinositol turnover in myometrium. The effect of phosphorylation of specific components on activity in the cell and in reconstituted artificial membranes will be explored and the effect of cell permeable protein kinase A anchor inhibitors on the ability of relaxin to inhibit G-protein-coupled phospholipase C will be determined. Aim 3 will determine the contribution of cAMP-mediated inhibition of G-protein stimulated phosphatidylinositol turnover in various stages of pregnancy in the rat. The ability of CPT-cAMP to inhibit OT-stimulated PI turnover during pregnancy in relation to expression and coupling of elements required to elevate cAMP will be determined. Aim 4 will determine the relationship between changes in ion channel activity, Ca release and Ca sequestration, and oxytocin-stimulated Ca(i) transients and oscillations in myometrial cells. The effect of perturbing these mechanisms on time-dependent changes in OT-stimulated Ca(i) transients and Ca(i) oscillations in single cells will be determined. Understanding these mechanisms is critical to the design of modalities to manage premature labor and dysfunctional labor, conditions which pose significant health risks for both mother and child.

描述（根据调查员的摘要改编）：总体 该提议的目的是了解分子机制 激素会影响子宫平滑肌收缩和放松。 AIM 1将阐明催产素受体（OTR）的贡献 细胞内环与相互作用的特异性和激活 GTP结合蛋白（G蛋白）。 受体嵌合体，特定地点 受体突变体以及过度表达的细胞内环的能力 抑制耦合的肽将用于检查OTR/G蛋白 互动。 AIM 2将定义cAMP抑制的机制 G蛋白刺激子宫肌层的磷脂酰肌醇周转。 这 特定成分磷酸化对细胞活性和活性的影响 将探索在重构的人造膜中 细胞渗透的蛋白激酶A锚定抑制剂在松弛蛋白的能力上 为了抑制G蛋白偶联的磷脂酶C，将确定。 目标3意志 确定CAMP介导的G蛋白的抑制作用 在怀孕的各个阶段刺激了磷脂酰肌醇周转率 大鼠。 CPT-cAMP抑制OT刺激的PI更新的能力 在怀孕期间与所需元素的表达和耦合有关 将确定抬高营地。 AIM 4将确定关系 离子通道活性的变化，CA释放和Ca固相之间的变化， 和催产素刺激的Ca（I）瞬时瞬变和振荡 细胞。 扰动这些机制对时间依赖性变化的影响 在OT刺激的Ca（i）瞬变和CA（i）振荡中 将确定。 了解这些机制对 设计如何管理早产和功能失调的劳动力的方式， 对母子构成重大健康风险的状况。