The Work of The Lab

The core interests of the APU group are autonomic neuroeffector mechanisms and receptor pharmacology, particularly of adrenoceptors. This is focussed mainly on how these work to control the cardiovascular system and how they malfunction in cardiovascular disease particularly hypertension, heart failure and stroke. The group has a growing and rekindled interest in human prostate and vas deferens respectively.

Adrenoceptor Pharmacology

Fluorescent Ligands: We have developed methods using fluorescent ligands to localise adrenoceptors in individual cells and in intact tissues. This has allowed quantification of drug-receptor interactions at the subcellular level and has uncovered functional binding of intracellular receptors, providing an important new concept for drug targetting. (ref. 420:)

MacKenzie, J.F, Daly, C.J., Pediani, J.D. & McGrath, J.C. (2000) Quantitative imaging in live human cells reveals intracellular alpha1-adrenoceptor ligand binding sites. J. Pharmacol. Exp. Ther. 294 (2) 434-443; also ref 423).

Transgenic Mice: Working with genetically modified mice, we are defining which receptors are responsible for vascular control and devising methods by which newly discovered receptors (arising from the genome project) can be investigated for their potential actions on autonomic control. This approach has also led to involvement with receptor analysis in the central nervous system since transgenesis affects the receptors wherever they are. (ref. 440):

Zuscik MJ, et al., (2001) Hypotension, autonomic failure, and cardiac hypertrophy in transgenic mice over-expressing the alpha1B-adrenergic receptor. J Biol Chem 276: 13738-13743: also ref. (392).

Vascular Structure Remodelling:

We are pioneering a new approach to studying tissue structure and function by combining vascular myography and confocal microscopy. This has shown, in hypertension and stroke, that blood vessel cells realign and change their intercellular relationships in ways that alter vascular function. (ref. 387) :

Arribas, S.M, Costa, R., Salomone, S., Morel, N., Godfraind, T. & McGrath, J.C. (1999) Functional reduction and associated cellular rearrangement in SHRSP rat basilar arteries are affected by salt load and calcium antagonist treatment. J. Cereb Blood Flow Metab. 19 (5) 517-527: also refs. 333, 348).

Quantifying 3D Vascular Structure: We are now combining this with receptor biology to to study vascular function, vascular remodelling, and receptor distribution & function (EC Framework V Project: Vascan 2000). We are seeking a quantitative analysis of the relationships between the vascular nerves, endothelium and smooth muscle supported by the Wellcome Trust Mathematics in Biology Scheme (ref. 426):

Shang, C., McGrath, J.C., Daly, C.J. & Barker, J. (2000) Modelling and classification of vascular smooth muscle cell images. Electronics Letters - IEE, 36 (18) 1532-1533.: also ref. 422).

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