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.
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