Professor Richard Callaghan
- Job title: Professor of Human Disease & Membrane Transport
- Email: R.Callaghan@leeds.ac.uk
- Faculty: Biological Sciences
- School: Biomedical Sciences
- Location: 6.108b Astbury
- Areas of expertise: ABC transporter mechanisms, Membrane transport, Reconstitution systems, Multidrug resistance in cancer, Tumour biology
- Website links: Google scholar | ORCID
Understanding transport processes at the cellular membrane is of high importance given the large number of diseases and pathologies caused by perturbations in transporter function. My team investigates membrane transport processes in relation to several pathologies including the drug resistant phenotype in cancer, the altered metabolic landscape in solid tumours, neurodegeneration pathways and genetic diseases of vision. Furthermore, the laboratory has recently begun to use our expertise in transport phenomena to investigate bacteria with a potential for bioremediation of polluted environments; an issue with significant societal importance and an area that biological sciences will play a major role. Investigation of membrane transporters is technically challenging and consequently, we are at the forefront of developing synthetic nanoscale systems to enhance research capability. Moreover, these nanoscale systems have considerable potential in biotechnology and synthetic biology applications for human health.
Current major projects
- molecular understanding of membrane transporters and how this can be exploited
- membrane transport activity in bacteria used for bioremediation
- amyloid peptide clearance in Alzheimer’s disease; linking pathology and behaviour
- developing synthetic nanopolymers to mimic biomembranes
Detailed research programme
Molecular understanding of membrane transporters and how this can be exploited
My laboratory has an extensive track-record investigating molecular mechanisms of multidrug efflux pumps, such as P-glycoprotein (Pgp), with the main objective of developing potent inhibitors at the pre-clinical level. We are focusing our attention to targeted medicinal chemistry approaches, developing compounds that avoid the clutches of Pgp and even compounds directed to the bioenergetic pathways underpinning its costly cellular activity. The powerful combination of biochemical and structural information is not restricted to Pgp or to multidrug pumps. Coupled with progress in the structural understanding of ABC proteins, understanding transporter mechanism will open the way to more rational and structure-informed drug design strategies for many types of transporters and their myriad associated diseases.
Membrane transport activity in bacteria used for bioremediation
We are investigating how an established heavy metal efflux pump (Atm1) enables cells to balance the need for sufficient iron levels whilst preventing a toxic overload. Preliminary biochemical data from my laboratory has revealed an interaction between iron-porphyrins with the transporter, and computational docking suggests an intriguing substrate-protein interaction. We are working on generating structural and biochemical information for this protein-substrate interaction and thereby fully elucidate the role of this transporter in iron homeostasis.
Amyloid peptide clearance in Alzheimer’s disease; linking pathology and behaviour
Alzheimer’s disease (AD) AD is caused by the deposition of amyloid (Aβ) peptides into plaques due to disruption of the delicate balance between the formation, degradation and removal of Aβ-peptides in the brain. We have recently identified the transporter responsible for the removal of Aβ-peptides from their site of synthesis; namely the neuronal cells and an age-dependent reduction in activity of this transporter is associated with Aβ-plaque formation. To explore this observation further, we have developed a versatile model of AD using transgenic C. elegans that recreates specific pathological features associated with Aβ-peptide toxicity. This investigative model will enable us to ascertain whether enhanced Aβ-peptide clearance prevents the behavioural dysfunctions associated with plaque formation and not simply the observed histopathology.
Developing synthetic nanopolymers to mimic biomembranes
Investigating membrane transporters, particularly those with substrate promiscuity and a penchant for hydrophobic ligands (e.g. drugs) remains a considerable challenge. Current investigative approaches are beset by technical limitations including low stability and unacceptably high permeability. Consequently, we are developing new experimental systems that use synthetic block co-polymers. Examples include (i) membrane mimetics containing native cellular components and resembling disc structures, and, (ii) hybrid polymer-lipid vesicular systems to enable vectorial transport measurements. The physical stability of polymer systems will enable their translation into a number of different applications including biotech applications such as drug discovery, development of protocells and nanorobots for drug delivery, local detoxification and synthetic bio-remediation.