REGULATION OF COLLAGENASE ACTIVITY IN THE UTERUS

子宫内胶原酶活性的调节

• 批准号: 6182224
• 负责人: JOHN J JEFFREY
• 金额: $ 31.17万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6182224
• 关键词: antisense nucleic acid; collagen; collagenase; enzyme activity; enzyme biosynthesis; enzyme induction /repression; enzyme mechanism; gene expression; genetic promoter element; genetic regulation; interleukin 1; interleukin 6; intermolecular interaction; laboratory rat; muscle cells; myometrium; neutralizing antibody; nucleoproteins; phenotype; protein isoforms; serotonin; smooth muscle; stromelysin; tissue /cell culture; uterus

The long-range goals of the studies supported by this grant over the years have been to define the mechanisms by which the pregnant and post-partum uterus regulates the metabolism of its principle connective tissue protein, collagen. This protein is absolutely required by the uterus for the structural integrity of the organ during pregnancy. Thus it is necessary to precisely regulate the amount and distribution of collagen in the tissue during gestation. After delivery, the protein is degraded during the rapid involution of the uterus occurring in all mammals. The degradation of collagen requires the action of a specific enzyme, interstitial collagenase, whose function it is to catalyze the cleavage in collagen which initiates the enzymatic degradation of the interstitial collagens. Our approach to these goals has been to obtain, in pure form, the molecules which are required for this process to occur in an orderly fashion, and to study the mechanisms by which they are controlled. Our studies have concentrated on the regulation of the gene for interstitial collagenase by the indoleamine serotonin. We have defined a major, new role for serotonin in myometrial smooth muscle cells: that of an obligatory activator of the gene for interstitial collagenase. In addition, we have identified serotonin as a multifunctional regulator of gene activation in the uterine myometrium. To date we have identified some fifteen genes regulated by serotonin in this cell. Of particular interest is the serotonin-dependent activation of interleukin-1 in these cells. We have shown that the induction of this cytokine is crucially required for the up-regulation of the interstitial gene. In the following years we propose to further elucidate the role of serotonin in the myometrial smooth muscle cell, to identify both the genes which are regulated as well as the mechanisms by which serotonin modulates the expression of these genes. Thus, we wish to examine specific elements in the promoters in a number of these genes which are required for serotonin- dependent gene regulation, in both positive and negative directions. It is our hope that, by defining the molecules involved in serotonin-mediated pathways, as well as the way in which their biological activity is regulated, normal pregnancy, labor and perinatal homeostasis can be better understood and more rationally managed. Moreover, it is anticipated that this information can also be applied to complicated pregnancies, in which fetal health may be endangered by uterine dysfunction.

多年来，这项赠款支持的研究的长期目标 已经确定了怀孕和产后 子宫调节其主要结缔组织的新陈代谢 蛋白质胶原蛋白 这种蛋白质是子宫绝对需要的， 怀孕期间器官的结构完整性。 因此 必须精确调节胶原蛋白的量和分布， 妊娠期间的组织。 分娩后，蛋白质降解 在所有哺乳动物子宫迅速退化的过程中。 的 胶原的降解需要特定酶的作用， 间质胶原酶，其功能是催化 胶原蛋白，其启动间质的酶促降解 胶原蛋白 我们实现这些目标的方法是，以纯粹的形式， 这个过程所需的分子 时尚，并研究其控制机制。 我们 研究集中在对间质性肿瘤的基因调控上， 胶原酶通过吲哚胺5-羟色胺 我们已经定义了一个主要的，新的 5-羟色胺在子宫平滑肌细胞中的作用： 间质胶原酶基因的强制性激活剂。 在 此外，我们已经确定血清素作为一种多功能调节剂， 子宫肌层中的基因激活。 到目前为止，我们已经确定了 在这个细胞中大约有15个基因受血清素的调控。 特别 感兴趣的是，在这些细胞中，白细胞介素-1的白细胞介素依赖性激活， 细胞 我们已经表明，这种细胞因子的诱导是至关重要的 这是间质基因上调所必需的。 在以下 多年来，我们建议进一步阐明血清素在 子宫肌层平滑肌细胞，以确定这两个基因， 调节以及血清素调节的机制， 这些基因的表达。 因此，我们希望审查以下方面的具体内容： 这些基因中的启动子是血清素所必需的， 依赖基因调控，在积极和消极的方向。 它 我们希望，通过定义参与胡萝卜素介导的 途径，以及它们的生物活性是如何 规范、正常的妊娠、产程和围产期的内环境能更好的稳定 理解和更合理的管理。 此外，预计 这一信息也可以应用于复杂的怀孕，其中 胎儿健康可能受到子宫功能障碍的危害。