The overall research program of the laboratory is directed towards advancing our understanding of the endocrine aspects of calcium homeostasis in vertebrates. In the current proposal, one of the principal hormones involved in calcium metabolism, parathyroid hormone (PTH), will receive major consideration. A comparative approach will be used involving both mammalian (rats and mice) and submammalian (Japanese quail) vertebrates. Where appropriate, attempts will be made to determine the revelance of in vitro findings with in vivo phenomena. The major thrust will be concerned with the structure-activity relationships between PTH and its receptors in an effort to examine the following hypothesis: That PTH effects its various responses through the mediation of more than one type of receptor. It is proposed to construct an extensive series of dose-response relationships to several PTH agonists and antagonists with respect to a wide spectrum of both in vivo and in vitro responses using rats, mice, and Japanese quail. Agonists will include untreated and oxidized forms of bPTH(1-34), bPTH(1-84), and porcine PTH(1-84), and untreated [N1e8,18, Tyr34]-bPTH(1-34)amide. Antagonists will include [N1e8,18, Tyr34]-bPTH(3-34)amide, [Tyr34]-bPTH(7-34)amide, and any other promising PTH antagonists which subsequently become available. Three potential target tissues of PTH, namely bone, kidney and gut, will be selected for investigation. In vitro assay models will include: neonatal mouse and Japanese quail calvarium tissue culture systems; and renal adenylate cyclase activity. In vivo model will include: hypercalcemic response in rats and Japanese quail; plasma 45Ca specific activity in animals which have been acutely or chronically labelled with 45Ca; urinary calcium, phosphorus, cAMP, and hydroxyproline responses; intestinal active transport of calcium, plasma 1,25-dihydroxyvitamin D responses and renal 25-hydroxyvitamin D3-1-hydroxylase activity; calvarial cAMP and enzyme contents; and osteoclast activation in avian medullary bone. Using this approach, patterned after that used by Ahlquist (1948) in his historic classification of the adrenergic receptors into Alpha and Beta components, it may be possible to categorize the receptors responsible for mediating the various responses to PTH into two or more classes. Such a classification, if successful, would have far-reaching physiological, pharmacological, and clinical implications.
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