FUNCTIONS OF PLACENTAL PROLACTINS

胎盘催乳素的功能

基本信息

批准号：
2199209
负责人：
DANIEL I LINZER
金额：
$ 10.64万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-08-01 至 1998-05-31
项目状态：
已结题

项目摘要

The purpose of the proposed research is to investigate the functions of the placental members of the prolactin/growth hormone family in the mouse. Since prolactin has a broad spectrum of activities in animal physiology, these related placental hormones are likely to be important regulators of the physiological changes that occur during pregnancy. Four placental members of the prolactin/growth hormone family have been identified in the mouse. We hypothesize that the interactions of these hormones with their receptors are important in regulating maternal physiology, fetal development, and the successful completion of gestation in the mouse. We propose to prevent the synthesis of one of these placental hormones (placental lactogen II) by generating a mouse strain in which the gene encoding this protein has been disrupted. Since this protein (as well as placental lactogen I) binds to the same receptor that recognizes prolactin, we will investigate the locations, timing, and levels of prolactin receptor expression in the developing mouse fetus. We will also generate mice that have a mutated gene for the prolactin receptor; this will test if the interaction of this receptor with these two placental hormones is essential for normal fetal development. If mice that lack the prolactin receptor are able to develop, then these mice would be of value in investigating the requirement for this receptor in such processes as growth and metabolism, reproduction, osmotic balance, lung development, and immune response in the adult. Two of the placental members of the prolactin/growth hormone family in the mouse do not bind to either the prolactin receptor or the growth hormone receptor, and their physiological roles and targets have not been defined. Our recent data indicate that physiological concentrations of these two proteins regulate angiogenesis: one of these proteins (proliferin) stimulates angiogenesis, while the other (proliferin-related protein) inhibits this process. We therefore hypothesize that these proteins play important roles in initiating and limiting placental angiogenesis and that they bind to specific receptors present on capillary endothelial cells. The actions of these two placental hormones in regulating angiogenesis will be further characterized, and the receptors through which these hormones act will be identified. In addition, we hypothesize that the expression of proliferin may occur in tumors, with this hormone then acting as a paracrine angiogenesis factor that promotes tumor growth and metastasis. By introducing an expression construct for proliferin into tumor cells, we will determine if we can increase the tumorigenicity of these cells. Similarly, the effect of expression of proliferin-related protein will be tested as a possible means of inhibiting angiogenesis, and therefore the growth, of tumors.

拟议研究的目的是研究小鼠中催乳素/生长激素家族的胎盘成员。由于催乳素在动物生理学中具有广泛的活性，因此这些相关的胎盘激素可能是怀孕期间发生的生理变化。四个胎盘催乳素/生长激素家族的成员已在老鼠。我们假设这些激素与它们的相互作用受体在调节孕产妇生理，胎儿很重要开发以及在鼠标中成功完成妊娠。我们提议防止合成这些胎盘激素之一（胎盘乳原II）通过产生基因的小鼠菌株编码该蛋白质已被破坏。由于该蛋白质（以及胎盘乳原I）与识别的同一受体结合催乳素，我们将调查位置，时机和水平在发育中的小鼠胎儿中催乳素受体的表达。我们也会产生对催乳素受体突变基因的小鼠；这将测试该受体与这两个胎盘的相互作用是否相互作用激素对于正常的胎儿发育至关重要。如果缺乏的老鼠催乳素受体能够发育，然后这些小鼠有价值在调查该受体的要求中生长和代谢，繁殖，渗透平衡，肺发育，成人的免疫反应。催乳素/生长激素家族的两个胎盘成员小鼠不与催乳素受体或生长激素结合受体及其生理作用和靶标尚未定义。我们最近的数据表明，这两个的生理浓度蛋白质调节血管生成：这些蛋白质之一（增殖蛋白）之一刺激血管生成，而另一个（增殖蛋白相关蛋白）抑制这一过程。因此，我们假设这些蛋白质发挥了在启动和限制胎盘血管生成中的重要作用，它们与毛细管内皮细胞上存在的特定受体结合。这两种胎盘激素在调节血管生成中的作用将进一步表征，以及这些受体将确定激素法。此外，我们假设然后，这种激素的表达可能发生在肿瘤中充当旁分泌血管生成因子，可促进肿瘤生长和转移。通过将增殖蛋白的表达构建体引入肿瘤细胞，我们将确定是否可以增加这些细胞。同样，增殖蛋白相关的表达的影响蛋白质将作为抑制血管生成的可能手段进行测试，并且因此，肿瘤的生长。