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Control of Parathyroid Hormone Secretion


Project Description

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 and cAMP imaging) as well as cell transfection with receptors, signalling modulators and siRNAs for selectively knocking down expression of CaR signal regulators.

Training/techniques to be provided:

Intracellular signalling measured using a) FRET-based cell imaging and b) Epifluorescence microscopy
Cell culture, transfection, gene knockdown and cell assay.
Molecular techniques including Immunoblotting, Immunofluorescence, RT-PCR and mutagenesis
Use of receptor allosteric modulators and consideration of GPCR signal and tissue bias.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References


[1] Campion KL, McCormick WD, Warwicker J, Bin Khayat ME, Atkinson-Dell R, Steward MC, Delbridge LW, Mun H-C, Conigrave AD, Ward DT. (2015) Pathophysiological Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism. Journal of the American Society of Nephrology. 26, 2163-2171.

[2] Conigrave AD, Ward DT (2013) Calcium-sensing receptor (CaSR): Pharmacological properties and signaling pathways. Best Practice & Research Clinical Endocrinology & Metabolism 27, 315-331.

[3] Yarova PL, Stewart A, Sathish V, Britt Jr RD, Thompson MA, Lowe APP, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K, Chang W, Bin Khayat ME, Ward DT, Corrigan CJ, Ward JPT, Kemp PJ, Pabelick CM, Prakash YS, Riccardi D (2015) Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Science Translational Medicine 7(284):284ra60.

[4] 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.

[5] 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.

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