Development of methods for mass production of recombinant growth hormone (GH) and for introduction of GH genes into mammalian embryos is certain to lead to widespread use of GH in medicine and agriculture. In this context it is important to understand the effects of chronic GH exposure on neuroendocrine function. Transgenic mice which express human or bovine GH genes exhibit various abnormalities in the function of catecholaminergic neurons in the hypothalamus, in the release of several hormones (including prolactin [PRL] and luteinizing hormone [LH]) from the pituitary and in female and male fertility. The broad objectives of the proposed studies are (i) to elucidate the mechanisms of GH action on the hypothalamic-adenohypophyseal function in transgenic animals, and (ii) to identify domains of the GH gene responsible for the various effects of chronic GH excess on neuroendocrine function and fertility. We will examine turnover rate, binding, uptake and release of dopamine (DA) and norepinephrine (NE) in various regions of the hypothalamus in transgenic mice expressing bovine GH (bGH) or human GH (hGH) genes and in normal mice treated with bGH. We will also examine hypothalamic secretion of LHRH and pituitary secretion of LH, FSH and PRL in these animals and relate the observed changes to gonadal function and fertility. The suspected cause:effect relationships will be probed with various adrenergic and dopaminergic agonists and antagonists in vivo and in vitro. Site-directed in vitro mutagenesis will be used to systematically convert designated segments of the bGH gene to the hGH gene and vice versa. These mutant genes will be combined with mouse metallothionein-I promoter and used to produce transgenic mice. Studies of neuroendocrine function in these animals will relate specific changes in the hypothalamic-hypophyseal function to defined domains of the GH gene. Results of these studies will produce new information on the mechanisms of GH action, on hypothalamic changes responsible for endocrine abnormalities of transgenic animals expressing various GH genes and on the functions of specific domains of the GH gene and by implication, the GH molecule. This information is needed for rational use of recombinant GH and of transgenic technology in medicine and agriculture.
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