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The mineral and bone disorders of chronic kidney disease (CKD-MBD) cause vascular calcification and cardiovascular
mortality in patients suffering advanced renal disease. CKD-MBD involves hyperphosphataemia (high serum phosphate) and secondary hyperparathyroidism (SHPT; excess parathyroid hormone release) which increase mortality in dialysis patients. However, the mechanism by which hyperphosphataemia increases parathyroid hormone (PTH) secretion remains unknown. The calcium-sensing receptor (CaR) is the key controller of PTH secretion, and we have identified CaR as the likely parathyroid phosphate sensor (Centeno et al., 2019). Specifically, raising phosphate concentration within the pathophysiologic range for CKD appears to inhibit CaR activity by non-competitive antagonism. More recently, we reported that a calcimimetic drug (that lowers PTH secretion in CKD) sees its effect impaired when the patient also has hyperphosphataemia (Goodman et al., 2022). Therefore, to better treat CKD-MBD we need to understand how hyperphosphataemia inhibits the calcium-sensing receptor – the critical controller of PTH secretion.
Another feature of CKD-MBD is vitamin D3 deficiency which is itself a common public health problem worldwide that is increasingly believed to contribute not only to decreased bone mineralisation but potentially to other serious medical conditions. Interestingly, there is even increasing evidence of links between obesity and vitamin D3 deficiency. However, the mechanisms underlying these associations remain poorly understood. This project will thus also look at the cellular actions of 1,25(OH)2 vitamin D3 formation on cells/tissues of the endocrine system.
The techniques involved in this project include hormone assay, live cell calcium imaging, kinase assays and transfection with siRNAs for the selective knockdown of calciotropic signal regulators. We will also perform ex vivo hormone assays on transgenic mouse parathyroid glands (modified by CRISPR/Cas9).
Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a related area/subject. Candidates with Masters-level experience in molecular and/or in vivo techniques are strongly encouraged to apply.
Eligibility
Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How to Apply
To be considered for this project you MUST submit a formal online application form – on the application form select PhD Pharmacology Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester
If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk
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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester
Funding Notes
Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/
References
[1] Centeno PP, Herberger A, Mun H-C, Tu C, Nemeth EF, Chang W, Conigrave AD, Ward DT (2019) Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion. Nature Communications. 10, 4693.
[2] Goodman WG, Ward DT, Martin KJ, Drayer D, Moore C, Xu J, Lai J, Chon Y, Nemeth EF (2022) Activation of the Calcium Receptor by Calcimimetic Agents is Preserved Despite Modest Attenuating Effects of Hyperphosphatemia. Journal of the American Society of Nephrology. 33, 201-212.
[3] 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.
[4] Centeno PP, Binmahfouz LS, Alghamdi K, Ward DT (2023) Inhibition of the Calcium-Sensing Receptor by Extracellular Phosphate Ions and by Intracellular Phosphorylation. Frontiers in Physiology. 14, 1154374.
[5] Leach K, Hannan FM, Josephs TM, Keller AN, Møller TC, Ward DT, Kallay E, Mason RS, Thakker RV, Riccardi D, Conigrave AD, Bräuner-Osborne H. (2020) International Union of Basic and Clinical Pharmacology: Calcium-sensing receptor Nomenclature, Pharmacology, and Function. Pharmacological Reviews 72, 558-604
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