Dr Donald WardPhD, SFHEA

Senior Lecturer

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Research interests

Extracellular Calcium Homeostasis

Whole body calcium homeostasis is maintained by the regulated secretion of parathyroid hormone (PTH) under the control of the extracellular calcium-sensing receptor (CaR). Hypercalcaemia stimulates the CaR to suppress PTH secretion, while decreased blood calcium levels permit increased PTH secretion. The fundamental role of CaR in the regulation of PTH secretion / calcium homeostasis is seen most clearly in neonatal severe hyperparathyroidism where babies born with a homozygous, loss-of-function CaR mutation secrete a massive excess of PTH. This condition, usually lethal without parathyroidectomy, is analogous to the phenotype of CaR (-/-) null mice. However, the mechanism by which the CaR suppresses PTH secretion remains unclear and this represents a major focus of my research.

The CaR is a Class C G protein-coupled receptor and couples to Gq/11, Gi/o and G12/13 proteins resulting in signalling that includes intracellular Ca2+ mobilisation (see Figure 1), ERK phosphorylation, actin polymerisation and suppression of cAMP formation as well as feedback phosphorylation of the receptor’s intracellular domain.

Figure 1: Increasing intracellular calcium levels (red/pink colours) in HEK-293 cells before (left) and after (middle) CaR stimulation resulting in sustained calcium oscillations (right)

 

Figure 1: Increasing intracellular calcium levels (red/pink colours) in HEK-293 cells before (left) and after (middle) CaR stimulation resulting in sustained calcium oscillations (right)

 

I am seeking to clarify the differential intracellular signalling pathways by which the CaR is able to inhibit secretion in parathyroid cells, stimulate secretion in other cells such as thyroidal C-cells and pancreatic β cells and then regulate ion transport in the kidney.

I am also interested in the pharmacological stimulation of the CaR, as used currently in the treatment of secondary hyperparathyroidism, a serious complication of kidney. Calcification of blood vessels occurs in most renal patients and is associated with poor clinical outcomes. Thus, renal patients must be treated for mineral changes in their blood and calcification of their blood vessels as well as for the loss of their kidney function and drugs which stimulate the CaR may be used for this purpose. In addition, drugs which inhibit the CaR may eventually be employed clinically to stimulate bone formation in osteoporosis.

Together these studies employ cells from parathyroid gland as well as cell culture models of the kidney, thyroid, intestine and vasculature as well as cells artifically transfected with genes of interest (see Figure below).

Figure 3: HEK-293 cells transfected with Green Fluorescent Protein and co-stained with Phalloidin (red colour indicating actin filaments, left) or DAPI (blue colour indicating the nucleus, right)Figure 2: HEK-293 cells transfected with a Green Fluorescent Protein and costained with a red actin stain (left) or a blue nuclear stain (right)

 

 

 

Projects

Research and projects

No current projects are available for public display