Professor Ann Canfield (BSc, PhD) - postgraduate opportunities
Control of Parathyroid Hormone Secretion
The regulation of parathyroid hormone (PTH) secretion is of fundamental importance for calcium homeostasis and in mineral conditions affecting bone and the kidneys. Whilst it is clear that the calcium-sensing receptor (CaR) represents the key controller of PTH secretion by suppressing its secretion, the way the CaR works remains unclear. Indeed, it is still not clear how elevated intracellular calcium concentration (Ca2+i) appears to suppress PTH secretion in parathyroid gland while stimulating hormone / neurotransmitter secretion in many other cell-types. Furthermore, the pulsatility of PTH secretion, which is vital for bone formation, remains poorly understood. Therefore, this project aims to shed light on both the basic physiology of mammalian calcium homeostasis as well as helping us to understand the development of osteoporosis and CKD-MBD (bone mineral disease of chronic kidney disease). This project involves live cell imaging (including intracellular calcium imaging) as well as cell transfection with receptors, signalling modulators and siRNAs for selectively knocking down expression of CaR signal regulators.
-  Lazarus S, Pretorius C, Khafagi F, Campion KL, Brennan SC, Conigrave AD, Brown EM, Ward DT (2011) A novel mutation of the primary protein kinase C phosphorylation site in the calcium-sensing receptor causes autosomal dominant hypocalcemia. European Journal of Endocrinology 164, 429–435.
-  McCormick WD, Atkinson-Dell R, Campion KL, Mun H-C, Conigrave AD, Ward DT (2010) Increased Receptor Stimulation Elicits Differential Calcium-Sensing ReceptorT888 Dephosphorylation. Journal of Biological Chemistry 285, 14170-14177.
-  Davies SL, Ozawa A, McCormick WD, Dvorak MM, Ward DT (2007) Protein kinase C-mediated phosphorylation of the Ca2+-sensing receptor is stimulated by receptor activation and attenuated by calyculin-sensitive phosphatase activity. Journal of Biological Chemistry 282, 15048-15056.
-  Ward DT, Riccardi D (2012) New concepts in calcium-sensing receptor pharmacology and signalling. (Review) British Journal of Pharmacology 165, 35-48.
Effect of obesity and vitamin D3 deficiency on calciotropic control and vascular signalling.
Obesity and vitamin D3 deficiency represent two increasingly common public health problems because they are both risk factors for a wide variety of serious and even life-threatening conditions. Two such diseases, involving whole body calcium homeostasis, are osteoporosis and the vascular calcification of chronic kidney disease and there is increasing evidence of links between obesity and vitamin D3 deficiency and these conditions. However, the mechanisms underlying these associations remain poorly understood. This project will look at the cellular effects of obesity on parathyroid hormone secretion and 1,25(OH)2 vitamin D3 formation in extracellular calcium homeostasis. It will then further examine the consequences of obesity and vitamin D3 deficiency in intracellular signalling in cell models of the human vasculature. The techniques involved in this project include hormone assay, live cell calcium imaging, and transfection with siRNAs for the selective knockdown of calciotropic signal regulators.
- Wu-Wong JR (2009) Potential for vitamin D receptor agonists in the treatment of cardiovascular disease. Br J Pharmacol. 158, 395-412.
- Ward DT, Riccardi D (2012) New concepts in calcium-sensing receptor pharmacology and signalling.
- Br J Pharmacol. 165, 35-48.
- Grethen E, McClintock R, Gupta CE et al. (2011) Vitamin D and hyperparathyroidism in obesity. J Clin Endocrinol Metab. 96, 1320-1326.
- Alam MU, Kirton JP, Wilkinson FL, Towers E, Sinha S, Rouhi M, Vizard TN, Sage AP, Martin D, Ward DT, Alexander MY, Riccardi D, Canfield AE (2009) Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovascular Research 81, 260-268.
- McCormick WD, Atkinson-Dell R, Campion KL, Mun H-C, Conigrave AD, Ward DT (2010) Increased Receptor Stimulation Elicits Differential Calcium-Sensing ReceptorT888 Dephosphorylation. Journal of Biological Chemistry 285, 14170-14177.