Department of Pharmacology

Cell Biology ~ Proteomics & Calcium Biology

1.Our Biology
2.Our Research Technologies
3.Independent Publications

 

1. Our Biology

Cell Signalling

The mechanisms used to relay messages within cells are of intense biomedical interest. Complex signalling pathways underlie normal development and health of cells. Many diseases are associated with cell signalling anomalies. Numerous drugs target the principal signalling effectors, calcium and protein phosphorylation.
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Calcium biology

Calcium has many roles inside and outside cells necessitating strict regulation at different concentrations in various locations. Calcium signals are transmitted through cells as transient increases of calcium which normally is at a very low concentration in the cytosol (cellular fluid). Toxicity arises if these calcium elevations are too large or frequent. It is clear that excess calcium can lead to cell death but disease-related disruptions of calcium signalling are not well understood.
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Dental enamel cells

We initiated investigations of calcium handling in enamel cells questioning how they make such a highly-calcified product (tooth enamel is 40% calcium) without suffering the toxic effects of excess intracellular calcium.Of general biomedical value, this research model comprises epithelial cells that have an informatively elongate morphology and undergo functionally-distinct phases of development. Dentally, these cells are also central to the understanding of enamel biomineralization and defects; more information

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Current research focus

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2. Our Research Technologies

 

Molecular and cellular biology

We are using a broad range of experimental approaches from the DNA level (eg cDNA cloning, TaqMan PCR) through protein (eg 2-D gels, recombinant protein engineering), cellular (eg confocal microscopy) and physiological levels (eg transgenic mouse characterisation).

 

Proteomics and protein biochemistry

Our speciality is microscale protein biochemistry, a challenging area necessitated by the scarcity of enamel cells. Several novel findings have followed characterisation of proteins expressed by enamel cells ('proteome analysis') [review].

An online database (ToothPrint) of dental proteins has been established.

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3. Independent Publications

A. Enamel cell biology – how is bulk calcium handled safely?

We developed microscale proteomic approaches and characterised enamel epithelial cells from developing teeth in neonatal rats and mice. This information was used to investigate the mechanistic basis of calcium transport across enamel cells. Our findings contradicted the classical "calcium ferry" dogma and led to development of a new paradigm for transcellular calcium transport that we've named "calcium transcytosis". Increasingly it appears this organelle-based mechanism could be more generally applicable across biology.

B. Calbindins and calretinin – what do they do?

Calbindins and calretinin have been regarded classically as mobile calcium buffers in the cytosol and consequently they're widely investigated as potential medical targets (e.g. in calcium transport and neurodegeneration). Our investigations of these calcium-binding proteins contradicted this view and instead pointed to a role involving interactions with other proteins. These findings, which lead us to contemplate an alternative role in cell signalling, hold fundamental significance for calbindins as medical targets.

C. ERp29 – what does it do?

We discovered ERp29 during proteomic analysis of rat enamel cells, leading to the naming and first description of this ubiquitous resident of the endoplasmic reticulum (ER). The challenge since has been to figure out its functional role, bioinformatics having offered only limited insight. In a series of pioneering studies, we've gathered a variety of clues that collectively point to a novel "housekeeping" role of general importance, probably as a new type of chaperone. Now linked to a broad array of physiological processes and diseases including cancer, ERp29 holds broad potential as a medical target.

D. Other reports and articles

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