Cell Biology Research
Cell biology research in the School of Physiology and Pharmacology can be subdivided into three broad themes:
Cell signalling
The mechanisms of action and regulation of G-protein coupled receptors (GPCRs) is a major focus of research within the School. The molecular mechanisms of desensitisation and internalisation of GPCRs in the central nervous sytem, such as the μ-opiod receptor feature heavily in this work. For instance, the ability of morphine to induce tolerance was recently suggested to be due to poor μ-opiod receptor internalisation and re-sensitisation rather than over-activation (McPherson et al 2010). There is a long history of the study of metabotropic glutamate receptors, indeed the first report of their existence came from work here at Bristol. Current work focuses on the agonist- and non-agonist-induced internalisation of these receptors (for example, Lennon et al 2010). Outside of the CNS, the regulation of purinergic receptor trafficking and its role in platelet aggregation is leading to new insights into thrombosis, for example Nisar et al 2010.
Cell migration and repair
Unlike after birth, embryos repair wounds without scarring, using similar mechanisms to those used in cell migration during development. Part of the research within the School is directed at how immune system cells, such as macrophages, deal with these competing functions and how a hierarchy of migratory cues allows them to prioritise between wound healing and development (for example Moreira et al 2010). This will hopefully lead to a better understanding of tissue repair, and thus wound healing, in adults.
Cell motility is a crucial aspect of both developmental and repair systems, ensuring that appropriate cellular growth and migration occurs in response to inflammatory cues. Research is particularly focused on ephrin receptors and their ligands, such as ephrin-B2. We have previously shown that eprin receptor activation regulatse the actin cytoskeleton during contact inhibition. However, recent work has indicated that endothelial cell morphology and motility is regulated by ephrin-B2 in a PDZ-domain dependent manner, but independently of ephrin receptors (Bochenek et al 2010). It has also been shown to be part of the vascular endothelial growth factor (VEGF) signalling pathway, which controls the growth of blood vessels and lymph vessels in development, repair and disease (Wang et al 2010).
CFTR modulation in health and disease
The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) transporter superfamily that forms a gated pathway for the passive movement of anions across cell membranes (see Huang and Sheppard 2009 for review of the gating properties). It plays a fundamental role in salt and water transport across epithelia in many tissues, a role that is highlighted by the devastating consequences of mutations, which cause the genetic disease cystic fibrosis. Partial loss of CFTR function in one organ system causes male infertility, chronic pancreatitis and bronchiectasis, conditions called CFTR-related diseases (Bombieri et al 2011, Journal of Cystic Fibrosis - in press). Thus understanding the roles played by CFTR and its regulation is crucial to understanding fully a variety of disease states and to develop rational new treatments for them. For instance, we recently showed that the CFTR channel is regulated directly by intracellular pH and identified the responsible molecular mechanisms (Chen et al 2009).