The long-term objectives of this research plan are to investigate at the cellular, biochemical, molecular and clinical levels five specific areas of current importance related to hormones that affect mineral ion homeostasis. Studies will focus on: 1. The newly discovered parathyroid hormone-related protein (PTHrP), its causative role in cancer hypercalcemia syndromes, its functions in non-neoplastic cells and in normal physiology, and its mechanism of action; 2. Mechanistic studies on parathyroid hormone action on osteoblasts, including functional roles of the cAMP and inositol lipid/Ca2+ transduction systems and characterization of the osteoblast-derived stimulator of osteoclastic bone resorption; 3. Direct actions of estrogens on human osteoblasts; 4. Novel actions of vitamin D (1,25(OH)2D3) on nonclassical target cells including regulation of calcium homeostasis and function in pituitary cells and keratinocytes; and 5. Cell biology and clinical studies on calcitonin with emphasis on the mechanism of action on osteoclasts, regulation of calcitonin secretion by extracellular Ca2+, and investigations on the very early diagnosis and genetic cause of hereditary medullary thyroid carcinoma (the MEN-2 syndromes). 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, pheochromocytoma, and the hypercalcemia of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK010206-27
Application #
3224679
Study Section
General Medicine B Study Section (GMB)
Project Start
1974-09-01
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
27
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Public Health
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Belinsky, G S; Tashjian Jr, A H (2000) Direct measurement of hormone-induced acidification in intact bone. J Bone Miner Res 15:550-6
Frolik, C A; Cain, R L; Sato, M et al. (1999) Comparison of recombinant human PTH(1-34) (LY333334) with a C-terminally substituted analog of human PTH-related protein(1-34) (RS-66271): In vitro activity and in vivo pharmacological effects in rats. J Bone Miner Res 14:163-72
Weilbaecher, K N; Hershey, C L; Takemoto, C M et al. (1998) Age-resolving osteopetrosis: a rat model implicating microphthalmia and the related transcription factor TFE3. J Exp Med 187:775-85
Fukayama, S; Royo, M; Sugita, M et al. (1998) New insights into interactions between the human PTH/PTHrP receptor and agonist/antagonist binding. Am J Physiol 274:E297-303
Barrett, M G; Belinsky, G S; Tashjian Jr, A H (1997) A new action of parathyroid hormone. receptor-mediated stimulation of extracellular acidification in human osteoblast-like SaOS-2 cells. J Biol Chem 272:26346-53
Goad, D L; Rubin, J; Wang, H et al. (1996) Enhanced expression of vascular endothelial growth factor in human SaOS-2 osteoblast-like cells and murine osteoblasts induced by insulin-like growth factor I. Endocrinology 137:2262-8
Monroe, J J; Tashjian Jr, A H (1996) Palytoxin modulates cytosolic pH in human osteoblast-like Saos-2 cells via an interaction with Na(+)-K(+)-ATPase. Am J Physiol 270:C1277-83
Monroe, J J; Tashjian Jr, A H (1996) Pretreatment with 17 beta-estradiol attenuates basal- and PTH-stimulated membrane adenylyl cyclase activity in human osteoblast-like SAOS-2 cells. Biochem Biophys Res Commun 225:320-5
Monroe, J J; Tashjian Jr, A H (1995) Actions of palytoxin on Na+ and Ca2+ homeostasis in human osteoblast-like Saos-2 cells. Am J Physiol 269:C582-9
Fukayama, S; Tashjian Jr, A H (1994) Involvement of alkaline phosphatase in the modulation of receptor signaling in osteoblasts: evidence for a difference between human parathyroid hormone-related protein and human parathyroid hormone. J Cell Physiol 158:391-7

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