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Mechanisms and roles of transport proteins at the blood-brain barrier, in red blood cells and in malarial parasites

Dr Margery A. Barrand (retired)

Downing College

e-mail: mb10002@cam.ac.uk

hladky.jpg

Dr Stephen B. Hladky (retired)

Jesus College

e-mail:


Tel: +44 1223 334019
Fax: +44 1223 334100

 

 

Keywords

Neurobiology, ion transport, multidrug efflux proteins, blood-brain barrier, erythrocytes, malarial parasites


Research Interests

The ATP Binding Cassette superfamily of proteins contains several members that act as transporters, so providing protection to cells and tissues against cytotoxic stresses. Past work by our groups has examined the mechanisms by which these transporters bring about transport of various different substrates, identifying the particular proteins involved, looking at their specific locations at the blood-brain barrier and factors regulating their expression under normal and pathological conditions. Regulatory factors include the influences of pH, hypoxic and oxidative challenge and signalling from other brain cell types. In a separate series of studies the functions of these transporters in red blood cells and in malarial parasites in the erythrocyte stages of their life cycle have been investigated. Other transporters of interest have been those regulating the ionic content of both endothelial cells at the blood-brain barrier and of malaria parasites. Determining if any of these transporters make good targets for therapeutic intervention has been a major aim and, in the context of erythrocyte stage malarial parasites, this work continues in collaboration with the group of Prof. Kiaran Kirk at ANU, Canberra, Australia. The current hypothesis is that one of the ABC transporters is the glutathione conjugate transporter that must exist in the parasite membrane.

Techniques that were employed in the above work included: tissue isolation; primary cell culture; molecular biological methods for modifying gene expression and for manipulating and analysing RNA, DNA and proteins; immunocytochemistry; transport studies with radiolabelled and with fluorescent tracers; visualising and quantifying intracellular distribution of fluorescent substrates, analysing intracellular pH and measuring ion channel activity using intracellular recordings.

Enquiries about any of our work current or past are welcome.

Publications:

Mokgokong R, Wang S, Taylor CJ, Barrand MA and Hladky SB (2013) Ion transporters in brain endothelial cells that contribute to formation of brain interstitial fluid. Pflügers Arch DOI: 10.1007/s00424-013-1342-9

Barrand MA, Winterberg M, Ng F, Nguyen M, Kirk K and Hladky SB (2012) Glutathione export from human erythrocytes and Plasmodium falciparum malaria parasites. Biochem J 448, 389-400.

Kania KD, Wijesuriya HC, Hladky SB and Barrand MA (2011) Beta amyloid effects on expression of multidrug efflux transporters in brain endothelial cells. Brain Res 1418, 1-11.

Robertson S, Mokgokong R, Kania KD, Guedj A-S, Hladky S and Barrand MA (2011). Nitric Oxide Contributes to Hypoxia-Reoxygenation-Induced P-Glycoprotein Expression in Rat Brain Endothelial Cells. Cell Mol Biol 31, 1103-1111.

Wijesuriya HC, Bullock JY, Faull RL, Hladky SB and Barrand MA (2010) ABC efflux transporters in brain vasculature of Alzheimer’s subjects. Brain Res 1358, 228-38.

Robertson SJ, Kania KD, Hladky SB and Barrand MA (2009) P-Glycoprotein expression in immortalized rat brain endothelial cells: comparisons after hypoxia-reoxygenation and after exogenously applied hydrogen peroxide. J Neurochem 111, 132-141

Lim JC, Mickute Z, Zaman M, Hopkins S, Wijesuriya HC, Steckler T, Moechars D, Van Leuven F, Sarnyai Z, Hladky SB and Barrand MA (2009) Decreased expression of multidrug efflux transporters in the brains of GSK-3β transgenic mice. Brain Res 1276, 1-10

Lim JC, Kania KD, Wijesuriya HC, Chawla S, Sethi JK, Pulaski L, Romero I, Couraud P-O, Weksler B, Hladky SB and Barrand MA (2008) Activation of β-catenin signaling by GSK-3 inhibition increases P-glycoprotein expression in brain endothelial cells. J Neurochem 106, 1855-1865.

Nicola PA, Taylor CJ, Wang S, Barrand MA and Hladky SB (2008) Transport activities involved in intracellular pH recovery following acid and alkali challenges in rat brain microvascular endothelial cells. Pflügers Arch 456, 801-812.

Millar I, Wang S, Brown PD, Barrand MA and Hladky SB (2008) Kv1 and Kir2 Potassium Channels Are Expressed in Rat Brain Endothelial Cells. Pflügers Arch 456, 379-391.

Lim JC, Wolpaw AJ., Caldwell MA., Hladky SB and Barrand MA (2007) Neural precursor cell influences on blood-brain barrier characteristics in rat brain endothelial cells. Brain Res 1159, 67-76

Taylor CJ, Nicola P, Wang S, Barrand MA and Hladky SB (2006) Transporters involved in regulation of intracellular pH (pHi) in primary cultured rat brain endothelial cells. J Physiol 576, 769-785.

Klokouzas A, Tiffert T, van Schalkwyk D, Wu C-P, van Veen HW, Barrand MA and Hladky SB (2004) Plasmodium falciparum expresses a multidrug resistance associated protein, Biochem Biophys Res Commun 321, 197-201.

Nwaozuzu OM, Sellers LA and Barrand MA (2003) Signalling pathways influencing basal and H2O2-induced P-glycoprotein expression in endothelial cells derived from the blood-brain barrier. J Neurochem 87, 1043-1051.

Klokouzas A, Wu, C-P, van Veen, H, Barrand MA and Hladky SB (2003) cGMP and glutathione-conjugate transport in human erythrocytes: the roles of the multidrug resistance-associated proteins, MRP1, MRP4 and MRP5. Eur J Biochem 270, 3696-3708.

 

Links to extended lists of publications:


http://www.ncbi.nlm.nih.gov/pubmed/?term=Barrand+MA%5BAuthor%5D
http://www.ncbi.nlm.nih.gov/pubmed/?term=Hladky+SB%5BAuthor%5D