Growth hormone (GH) release from the pituitary is controlled by a complex interaction between somatostatin (SS) and growth hormone-releasing hormone (GHRH). These two hypothalamic neuropeptides act in a push-pull fashion to produce a train of GH pulses with a frequency of about once every 3h. This ultradian patterning of GH pulses, which is important for the proper functioning of target tissues, including muscle and liver, changes over the course of development and undergoes significant alterations under various physiological and pathological states. The goals of this research are to understand the cellular physiology of the neural network that generates pulses of GH and to elucidate some of the molecular mechanisms by which hormones regulate the activity of the so-called """"""""GH pulse generator."""""""" First, we will focus on identifying the neuroanatomical substrate and molecular mechanisms by which GH and testosterone regulate the expression of the genes coding for SS and GHRH. We will map the distribution and cellular content of GH- and androgen-receptor message under different experimental paradigms. Second, we will focus on understanding the cellular physiology governing the GH pulse generator. We will test the hypothesis that GH rapidly influences the rate of SS and GHRH gene transcription by assessing the time course of GH effects, on SS mRNA and GHRH mRNA and by evaluating the influence of constant plasma GH levels on the generation of spontaneous GH pulses. We will also use """"""""dwarf"""""""" and """"""""little"""""""" mice (which manifest specific lesions of the GH/SS/GHRH control system) to examine the role that interconnections between SS and GHRH neurons play in the generation of pulsatile GH secretion. By using these molecular approaches to evaluate the regulation of GH secretion in vivo, we hope to gain insight into the neuroendocrine mechanisms underlying the episodic secretion of pituitary hormones. We believe this work will provide a better understanding of basic cellular neurobiology, which may be of use in solving problems related to growth abnormalities.
