REGULATION OF COLLAGENASE ACTIVITY IN THE UTERUS

子宫内胶原酶活性的调节

• 批准号: 3310361
• 负责人: JOHN J JEFFREY
• 金额: $ 26.31万
• 依托单位: WASHINGTON UNIVERSITY
• 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 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3310361
• 关键词: cell free system; collagenase; connective tissue metabolism; cyclic AMP; cyclic nucleoside monophosphate; enzyme inhibitors; enzyme mechanism; glucocorticoids; hormone regulation /control mechanism; human pregnant subject; human tissue; immunodiffusion; immunologic assay /test; laboratory rabbit; laboratory rat; mass spectrometry; messenger RNA; postpartum; pregnancy; progesterone; protein biosynthesis; protein sequence; radioimmunoassay; radiotracer; reproductive hormone; stoichiometry; tissue /cell culture; uterus

Our long range goals are to define, in specific chemical and physiologic terms, the mechanisms by which the pregnant and post-partum uterus regulates the metabolism of its principal 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 level and distribution of collagen in the tissue during gestation. After delivery, the protein is degraded during the general involution of the uterus occurring in all mammals. The degradation of collagen in the uterus absolutely requires the action of a specific collagenase, whose function it is to catalyze the crucial cleavages in collagen which initiate the process by which the protein is removed from the extracellular matrix. The specific approaches of these studies are to obtain, in pure form, the biological molecules which are required for this process to occur in an orderly fashion; these include the zymogen of collagenase itself, an activator of this zymogen, and an inhibitor of active collagenase, all of which are produced by the uterus for the purpose of regulating the rate and the direction of collagen degradation in the organ. These molecules are in the process of being purified, their chemical nature investigated, and their interactions studied. The results of these investigations should provide fundamental information regarding the mechanisms by which collagen degradation is accomplished in the uterus and, very likely, in other tissues as well. In addition, the physiologic processes by which the appearance of these molecules in the uterus is regulated will be studied in two principal in vitro systems: in cells and in organized explants in culture. The nature of the mechanisms whereby collagenase production and activity can be induced, modulated in situ, and terminated when no longer required are all under study. Such mechanisms involve the physiologic activities of important gestational hormones such as progesterone and relaxin, as well as the role of physical distension of the uterine myometrium as an important modifier of uterine connective tissue metabolism. By understanding the molecules involved in these processes and the way in which their giological activity is regulated, normal pregnancy can be better understood and more rationally managed. The information can also be applied to complicated pregnancies, in which fetal health may be endangered by uterine dysfunction.

我们的长期目标是确定，在特定的化学和生理 术语，怀孕和产后子宫 调节其主要结缔组织蛋白的代谢， 胶原 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，有必要 精确调节组织中胶原蛋白的水平和分布 在怀孕期间 递送后，蛋白质在递送期间降解。 所有哺乳动物子宫的退化。 降解 子宫中的胶原蛋白绝对需要一种特定的 胶原酶，它的功能是催化关键的裂解， 胶原蛋白，其启动蛋白质被去除的过程， 细胞外基质 这些研究的具体方法是 以纯净的形式获得所需的生物分子， 过程以有序的方式发生;这些包括 胶原酶本身，这种酶原的激活剂，和 活性胶原酶，所有这些都是由子宫产生的目的 调节胶原蛋白降解的速度和方向， 器官. 这些分子正在被纯化的过程中， 研究了它们的化学性质，并研究了它们的相互作用。 结果 这些调查应提供基本信息， 胶原蛋白降解在子宫内完成的机制 而且很有可能在其他组织中也是如此。 此外，生理 这些分子在子宫中出现的过程， 调节将在两个主要的体外系统中进行研究：在细胞中， 在有组织的外植体中培养。 机制的性质， 胶原酶的产生和活性可以被原位诱导、调节， 在不再需要时终止，所有这些都在研究中。 这种机制 涉及重要的妊娠激素的生理活动， 孕酮和松弛素，以及身体膨胀的作用， 子宫肌层作为子宫结缔组织的重要修饰物 组织代谢 通过了解参与这些过程的分子以及 它们的生物学活动受到调节，正常妊娠可以 更好地理解和更合理地管理。 这些信息同样可以 适用于可能危及胎儿健康的复杂妊娠 子宫功能障碍