Information

Research in epithelial transport

David Meredith MA DPhil

This laboratory works mainly on peptide transporters, both cloned and expressed in Xenopus oocytes and in cell lines such as Caco-2. We are interested in the mammalian proton-coupled peptide transporter PepT1, which is responsible for the majority of uptake of protein from the diet. We are particularly focussing on:

(i) How does PepT1 work as a molecule?

Currently there is no 3D crystal structure for PepT1, and so we are using site-directed mutagenesis to identify residues in the protein which are important for its function. We also are probing the shape of the binding site with unnatural substrates to investigate which parts of the protein are involved in substrate binding.

(ii) How is PepT1 regulated?

Many factors, including diet, regulate the way in which the intestine handles dietary nutrient absorption. We are interested in investigating the intracellular pathways that control the rate of peptide uptake, using the model cell line Caco-2.

Both (i) and (ii) are useful in addressing the following question:

(iii) Can we exploit PepT1 as a drug delivery route?

Prescribed drugs, such as antibiotics and anti-hypertension agents, are absorbed by PepT1 from the intestine despite not being endogenous substrates. We have developed a model for the substrate binding site for PepT1 that allows us to predict binding from the chemical structure. Further refinement of this model will allow the intelligent design/modification of drugs to be PepT1 substrates, and thus enable them to be taken orally.

In addition to the work on PepT1, I am also interested in membrane transporters that are involved in growth and development (in collaboration with Drs Wilson & Goberdhan) and in cartilage cells (chondrocytes, with Dr Wilkins). I am also interested in the involvement of membrane transporters in the endocrine system (in collaboration with Dr Christian and Professor Morris).

Current Funding: Wellcome Trust

Other activities: College Lecturer in Biomedical Science, St Anne’s College; departmental graduate studies committee.

Key Publications

Meredith D. (2004) Journal of Biological Chemistry, 279, 15795-8

Goberdhan DCI et al (2005) Development, 132, 2365-2375

Bailey PD et al, (2005) Chemical Communications 2005 (42), 5352-4

Bailey PD et al. (2005) Organic & Biomolecular Chemistry, 3, 4038-9

Bailey PD et al (2005) Chemical Communications 2006 (3), 323-5

Pantisas KE et al (2006) Pflugers Archiv, epub 8th Feb 2006

Main Collaborators:

Professor PD Bailey, Manchester
Professor G L Kellett, York
Dr Richard Boyd, Oxford

Dr Robert Wilkins, Oxford

Dr Helen Christian & Professor John Morris, Oxford

Dr Clive Wilson, Oxford

Dr Deborah Goberdhan, Oxford

Group Members:

Miss Myrtani Pieri (graduate student)