We propose to study the interactions among the calcitropic hormones, parathyroid hormone (PTH), calcitonin (CT) and 1,25 dihydroxycholecalciferol (1,25DHCC); their interactions with other hormones important in skeletal metabolism, such as gonadal and adrenal steroids; and their effects on their target organs. Studies will also be made of proteins and peptides related to the calcemic hormones, such as calcitonin-gene-related peptide (CGRP) and Endocrine Secretory Protein (ESP, a.k.a. PSP, SP-I, Chr A). The studies will be conducted in vitro and in vivo in humans and experimental animals. In vitro studies will be conducted in cell, tissue, and organ cultures which produce calcitonin, PTH, CGRP, and ESP. The effects of the calcitropic hormones on the skeletal system will be assessed by newly developed immunochemical procedures for measuring bone gla protein, bone alkaline phosphatase, matrix gla protein and osteonectin. Regulation in these systems will be evaluated by classical techniques as well as the new approaches of molecular biology. Hormone biosynthesis and secretion will be studied with in vitro models which can then be ued as the bases for the design of corresponding in vivo studies. In vivo studies in humans will be complemented by detailed studies in rats, selected studies in artiodactyls, and marine biology studies in fish representative of differing habitudes and skeletal systems. The studies will utilize extant and newly developed radioassays and related biochemical, immunochemical, and immunohistochemical procedures; many of these methods will be based on monoclonal antibodies. The hormone assay procedures will be designed to directly and indirectly assess biological activity. Monoclonal antibody technology and recombinant DNA procedures will also be used. Regulatory studies will be conducted of physiological variables such as gender and aging and of selected aspects of human disease states and relevant animal models. These disease states include hypercalciuria, hypercalcemia, William's syndrome, Paget's disease, renal osteodystrophy and osteoporosis. These studies of the interactions among the calcitropic hormones, their biosynthesis and secretion, their target organ effects, and their molecular biology should provide basic information and clinically useful data about their role in physiology and pathophysiology.
