The overall goal of this research project is to characterize the effects of potential regulators of parathyroid hormone (PTH) biosynthesis and secretion, particularly the active metabolite of vitamin D 1,25(0H)2D3, and attempt to define their modes of action at a molecular level. Central to this project has been the observation that both 1,25(OH)2D3 and calcium ion decrease the expression of the PTH gene. Recent results from studies in our laboratory have helped form the framework of the present study. 1.) The cloning and sequence analysis of the gene for avian parathyroid hormone was useful in identifying a sequence element in the 5' flanking sequence that is sensitive to inhibition by 1,25(OH)2D3 and binds the vitamin D3 receptor. This element will be characterized further in terms of identifying the precise sequence required for its function and how it interacts with other elements in the PTH promoter. Other regions of the avian gene will be examined for sequences that may be responsible for regulation by calcium. 2.) The observation that there is a strong interaction between 1,25(OH)2D3 and calcium in regulation of genes for both PTH and vitamin D receptor in the parathyroid gland. Studies will be conducted to characterize the mechanism of this interaction and to explore the relationship between non- genomic (calcium transport) and genomic effects of l,24(OH)2D3. 3.) The finding that, in bovine parathyroid cells, 1,25(OH)2D3 increases the gene expression and biosynthesis of Chromogranin A, which has shown to be a precursor for peptides that inhibit PTH secretion. The role of Chromogranin A, which has been shown to be a precursor for peptides that inhibit PTH secretion. The role of Chromogranin A in parathyroid gland function as well as the processing of the intact precursor to biologically active peptides in normal and abnormal parathyroid glands will be explored. 4.) The suggestion that there are biochemical differences which may be useful in distinguishing hyperplastic parathyroid glands from adenomas. Potential differences will be explored both from whole tissue extracts and from secreted products.
| Ishimi, Y; Russell, J; Sherwood, L M (1990) Regulation by calcium and 1,25-(OH)2D3 of cell proliferation and function of bovine parathyroid cells in culture. J Bone Miner Res 5:755-60 |
| Sherwood, L M; Russell, J (1989) The role of 1,25-(OH)2D3 in regulating parathyroid gland function. Proc Soc Exp Biol Med 191:233-7 |
| Leiser, M; Sherwood, L M (1989) Calcium-binding proteins in the parathyroid gland. Detailed studies of parathyroid secretory protein. J Biol Chem 264:2792-800 |
| Feinfeld, D A; Sherwood, L M (1988) Parathyroid hormone and 1,25(OH)2D3 in chronic renal failure. Kidney Int 33:1049-58 |
| Russell, J; Sherwood, L M (1987) The effects of 1,25-dihydroxyvitamin D3 and high calcium on transcription of the pre-proparathyroid hormone gene are direct. Trans Assoc Am Physicians 100:256-62 |
