The long-term objectives of this research plan are to investigate at the cellular, biochemical and molecular levels three specific areas of importance related to hormones that affect mineral ion metabolism. Studies will focus on: 1. mechanisms of action of bone resorption-stimulating factors (PTH, PGE2 and specific growth factors). Experiments will emphasize actions on Ca2+ metabolism in isolated bone cells, and regulation of protein phosphorylation, protein kinase activity, phospholipid and arachidonic acid turnover. 2. Vitamin D action in a new model system. The molecular mechanisms by which 1,25(OH)2D3 and Ca2+ act interdependently to regulate expression of the prolactin gene and prolactin synthesis will be examined in clonal strains of rat pituitary cells in culture. 3. Calcitonin. Studies on the early actions of calcitonin on isolated bone cells in culture will parallel and contrast with those of bone resorption-stimulating factors on cellular Ca2+ metabolism, protein phosphorylation and phospholipid turnover. In addition, the mechanism by which Ca2+ directly enhances calcitonin secretion by clonal strains of C-cells will be investigated. In the human medullary thyroid carcinoma syndrome, new diagnostic and prognostic studies will involve radioimmunoassay, immunocytochemistry, somatic and tumor cell culture, and chromosomal analysis. The experiments proposed are designed to investigate several fundamental aspects of hormones affecting mineral metabolism and to relate these findings to clinically important disorders of bone metabolism in the human including osteoporosis, hyperparathyroidism and the hypercalcemias of cancer.
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