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Control of Parathyroid Hormone Secretion


   Faculty of Biology, Medicine and Health


Manchester United Kingdom Biochemistry Endocrinology Medicine Pharmacology Physiology

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 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.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience, particularly in cell culture and molecular biology, are particularly encouraged to apply.

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Genetics

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/”

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk


Funding Notes

Applications are invited from self-funded students. 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).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

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] Binmahfouz LS, Centeno PP, Conigrave AD, Ward DT. (2019) Identification of Serine-875 as an Inhibitory Phosphorylation Site in the Calcium-Sensing Receptor. Molecular Pharmacology. Jun 12. doi: 10.1124/mol.119.116178

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

[4] Roberts MS, Gafni RI, Brillante B, Guthrie LC, Streit J, Gash D, Gelb J, Krusinska E, Brennan SC, Schepelmann M, Riccardi D, Bin Khayat ME, Ward DT, Nemeth EF, Rosskamp R, Collins MT (2019) Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635). Journal of Bone & Mineral Research May 7. doi: 10.1002/jbmr.3747

[5] 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

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