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Geoffrey N. Hendy, Ph.D., Professor, Department of Medicine, |
Research:
The parathyroid gland and its two major secretory products: parathyroid hormone (PTH) and chromogranin A (CgA).
The work of my laboratory is focused on understanding parathyroid function in health and disease at the molecular level. The modulation of PTH and CgA synthesis in parathyroid cells in response to calcium and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] has been defined at different levels including gene transcription and mRNA stability. A novel effect of 1,25(OH)2D3 on CgA mRNA translatability was discovered. My laboratory cloned and characterized the human CgA gene and defined a minimal gene promoter region responsible for its neuroendocrine cell-specific expression. We provided strong evidence that the mammalian subtilisin-like proprotein convertases, furin and PC7, are the enzymes responsible for the physiological cleavage of the precursor molecule proPTH to yield mature PTH. Molecular genetic techniques are being used to search for and characterize mutations in genes important for parathyroid function. For example, novel mutations in the calcium-sensing receptor gene have been defined in patients with Familial Hypocalciuric Hypercalcemia (FHH) and Neonatal Severe Hyperparathyroidism (NSHPT).
Selected Publications:
Bai, M., Janicic, N., Trivedi, S., Quinn, S.J., Cole, D.E.C., Brown, E.M., Hendy, G.N. Markedly reduced activity of mutant calcium-sensing receptor with an inserted alu element from a kindred with familial hypocalciuric hypercalemia and neonatal severe hyperparathyroidism. J. Clin. Invest. 99: 1917-1925, 1997.
Canaff, L., Bevan, S., Wheeler, D.G., Mouland, A.J., Rehfuss, R.P., White, J.H., Hendy, G.N. Analysis of molecular mechanisms controlling neuroendocrine cell specific transcription of the chromogranin A gene. Endocrinol. 139: 1184-1196, 1998.
Lazure, C., Gauthier, D., Jean, F., Boudreault, A., Seidah, N.G., Bennett, H.P.J. and Hendy, G.N. In vitro cleavage of internally quenched fluorogenic human proparathyroid hormone and parathyroid hormone-related peptide substrates by furin: generation of a potent inhibitor. J. Biol. Chem. 273: 8572-8580, 1998.
Cole, D.E.C., Peltekova, V.D., Rubin, L.A., Hawker, G.A., Vieth, R., Liew, C.C., Hwang, D.M., Evrovski, J., and Hendy, G.N. Association of the A986S polymorphism of the calcium-sensing receptor with circulating calcium concentrations. Lancet. In Press. 1998.