About the Project
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.
Funding Notes
This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.
References
• [1] Ward DT, Mughal MZ, Ranieri M, Dvorak MM, Valenti G, Riccardi D (2013) Molecular and Clinical Analysis of a Neonatal Severe Hyperparathyroidism Case Caused by a Stop Mutation in the Calcium-Sensing Receptor Extracellular Domain Representing in Effect a Human “Knockout”. Eur J Endocrinol. 169, K1-7
• [2] 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. Eur J Endocrinol. 164, 429–435.
• [3] McCormick WD, Atkinson-Dell R, Campion KL, Mun H-C, Conigrave AD, Ward DT (2010) Increased Receptor Stimulation Elicits Differential Calcium-Sensing ReceptorT888 Dephosphorylation. J Biol Chem 285, 14170-14177.
• [4] 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. J Biol Chem 282, 15048-15056.
• [5] Conigrave AD, Ward DT (2013) Calcium-sensing receptor (CaSR): Pharmacological properties and signaling pathways. (Review) Best Practice & Res Clin Endocrinol & Metab 27, 315-331.
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