Institute of Biological and Biomedical Sciences
Cell Biology and Pharmacology
Research in the Cell Biology and Pharmacology Group encompasses research at the molecular, cell, organ system and whole animal level in health and disease. Our research is both fundamental and translational, with a focus on both understanding molecular mechanisms of disease and developing new therapeutic approaches.
Current research themes include neurobiology and the role of non-neural glial cells and axon-glial interactions in the central nervous system, cell and molecular neuro-oncology, focussing on the cellular and molecular mechanisms which underlie the migration of tumour cells and their invasion of normal brain tissue, neurochemical anatomy, neuropsychopharmacology and neuropharmacology relating to stress, food intake and obesity.
Ion channel studies include the electrophysiology and structure-function relationship of potassium channels in human neural cell biology and microbes, as well as the role of the CFTR chloride ion channel in inflammation. Inflammation research investigates mechanisms and biomarkers of inflammatory disease in the lung, skin, bladder and bowel as well as systemic inflammation and diabetes research. In parallel, research by the Clinical Pharmaceutics group investigates the particle size of drugs nebulised for delivery to the airways and the chemical and physical stability of combinations of drugs for intravenous use in these and other disorders.
Much of our research is carried out in collaboration with Consultant specialist physicians and the Pharmacy Department at Southampton General Hospital and the Queen Alexandra Hospital in Portsmouth.
Our current research
The primary areas of research are neuroglial cell biology led by Professor Arthur Butt and the functions of the locus coeruleus (LC) in stress, led by Dr Jerome Swinny, with an important emphasis on the ageing brain. We are applying electrophysiological, anatomical, imaging, molecular biological and behavioural techniques to understand the roles of ion channels and neurotransmitters in the pathophysiology of neurones and glia in stress, multiple sclerosis, stroke and cognitive decline in the ageing brain. We are particularly interested in the functions of potassium channels and GABA receptors. We have identified important functions for inward rectifying and two-pore potassium channels in normal brain function and in the integrity of oligodendrocytes, the myelin-forming cells of the CNS.
Further, in a collaborative project with Dr Sassan Hafizi we are examining the role of Gas6 in myelination. We are studying the biophysics and regulation of neuronal and glial potassium channel proteins and their roles in the cellular physiology of human health and disease. Another key area is the role of neurotransmitter and growth factor signalling pathways such as Wnt in regulating neurogenesis and oligodendrogenesis. One of our main areas of expertise is on the function of GABA receptors in the LC and we are particularly interested in how psychosocial stress confers either vulnerability or resilience to developing mental illnesses. We aim to understand the roles of particular GABA-AR subtypes in addicitive behaviour, and the functional plasticity of the LC-noradrenergic system in Alzheimer’s Disease and mood disorders. We are also collaborating with Dr James Brown to examine the functions of GABA and glia in the enteric nervous and their roles in stress-induced GI disorders.
Cellular and Molecular Neuro-oncology
There is currently no cure for gliomas, an aggressive brain tumour derived from glial cells. Our primary research, led by Professor Geoff Pilkington, focusses on the cellular and molecular mechanisms that underlie the migration of tumour cells and their invasion of normal brain tissue. We aim to understand how gliomas and other intracranial tumours interact, move and invade through the normal brain and investigate how brain tumours maintain growth and progression in the normal brain, by studying blood vessel formation and the complex relationship to hypoxia. We also study the metastatic spread of cancers into the brain and identify how brain tumours maintain self-renewal and development by studying rare populations of brain tumour stem cells.
With Dr Sassan Hafizi we are also investigating the role of AXL receptor tyrosine kinase stimulation by its ligand, Gas6, in cancer cell proliferation and migration. We wish to identify how each of these mechanisms sustain the aggressive growth of brain tumours, and how therapeutically targeting these mechanisms might result in tumour cell death (apoptosis) and degeneration. Once candidate "target" molecules have been identified, anti-invasive and pro-apoptotic translational medicine approaches are used in an attempt to formulate novel therapies, aimed at improving survival times and quality of life for patients. This could potentially lead to cures for the many different histological types of tumour that are included in this category of primary or intrinsic brain tumours.
Inflammation is central to most disease processes and we have a number of research interests with a common theme of understanding the underlying processes of inflammation and developing new methods for their treatment. Our primary interests are in respiratory immunopharmacology, diabetes and inflammatory bowel disease. Research led by Professor Janis Shute is investigating mechanisms of inflammation, tissue damage and repair in respiratory diseases, including cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). Our focus is on the role of CFTR in lung microvascular endothelial cells in regulation of the inflammatory response in cystic fibrosis lung disease, the role of fibrin formation in the airways in asthma and the pharmacological regulation of elastin and collagen synthesis by lung fibroblasts in COPD. The group are currently developing biomarker assays, using clinical samples from patients with severe asthma, to monitor disease progression and response to therapy, and to predict the on-set of an asthma attack.
In addition, we are investigating novel mucolytic, anti-oxidant, anti-bacterial and anti-inflammatory properties of heparin for novel therapeutic applications in the treatment of obstructive airways disease. The Dysglycaemia, Oxidative stress and the Vascular Endothelium (DOVE) Project is a collaboration with local hospitals, led by Dr David Laight to examine the roles and interactions of both traditional and non-traditional metabolic and cardiovascular risk factors in diabetes mellitus. In addition, Dr James Brown is working closely with the Portsmouth NHS Trust hospitals and the neuroscience group to understand gastrointestinal dysfunction and mechanisms of disease progression, with particular emphasis on inflammatory bowel disease and dysplasia.
Mammalian and Fungal ion channels
The ion channel group, led by Dr Anthony Lewis, is studying the biophysics and regulation of membrane potassium channel proteins and their roles in the cellular physiology of human health and disease. We are employing a combined mutagenesis and electrophysiological approach to study structure-function behaviours in mammalian potassium channels, and we employ a combined mutagenesis and electrophysiological approach to study structure-function behaviours in mammalian potassium channels. We are currently collaborating with Professor Arthur Butt in a study characterising a novel potassium channel, Kir7.1, in neural cell development.
Opportunistic fungal pathogens are a major cause of life-threatening infections in individuals with a compromised immune system, including HIV/AIDS patients, those undergoing blood and marrow transplant, major surgery or receiving chemotherapy and resistance to traditional interventions such as fluconazole is a growing problem, hence the search for novel anti-fungal targets is critical. We have recently identified and cloned a number of potassium channels from several species of human pathogenic fungi which represent the primary sources of fatal infections in the immunosuppressed population (Candida albicans, Aspergillus fumigatus and Cryptococcusneoformans). These potassium channels, called TOK1 for Two-pore Outwardly rectifying K+ channel, are unique in that they have no known structural or functional homologues in either mammals or plants, and are the only potassium-selective ion channel expressed in yeast and fungi, making them ideal candidates for future antimicrobial compounds. We use electrophysiological and genetic techniques to provide a greater understanding of channel function and how they may be targeted with anti-fungal therapies that may be applied to agricultural and medical areas.
Research led by Dr Ivor Ebenezer is investigating the neural regulation of appetite, food intake and energy homeostasis. It is well established that leptin is involved in the control of long-term energy homeostasis and we are currently looking at the way in which leptin may act with other gut peptides, such as cholecystokinin (CCK), to orchestrate short-term satiety. In addition, we are examining the function of central GABA-B receptors and the regulation of short-term food intake and long term energy homeostasis. We have shown that GABA acts at central GABA-B receptors to play a physiological role in the regulation (initiation) of food intake.
As part of the European Union Inter Reg TransChannel Neuroscience Network (TC2N), we are collaborating with Professor Sergueï O. Fetissov and his colleagues at Institute for Research and Innovation in Biomedicine (IRIB) (Rouen University, France) on the role of GABA in the regulation of feeding and the role that auto-antibodies generated to gut bacteria may play in the genesis of obesity. We are also investigating the underlying mechanisms involved in 5-hydroxytryptamine (serotonin) mediated control of short-term food intake and body weight, understanding the neural mechanisms involved in the control of fluid intake, and developing methods to assess potential antidepressant activity in novel pharmacological compounds.
The Bladder Disease group, led by Dr John S. Young, is investigating highly prevalent but poorly treated pathologies of the urinary bladder. In studying the origins and progression of disease, their aim is to highlight new targets for improved management of otherwise debilitating symptoms. Previous research elucidated a signal transduction pathway responsible for our perception of bladder fullness; identifying new targets for modulating this pathway that will ultimately lead to better management of urinary urgency. We have also studied the origins and spread of communication within the bladder wall, and how mechanisms are affected in disease; an essential first step to treating detrusor overactivity. Building on these studies, we have been developing novel, cheap, non-invasive techniques to diagnose disease at an earlier stage than current diagnostic methods allow. This is highly pertinent given that the diagnosis of many bladder pathologies is either imprecise (questionnaires of urinary symptoms) or expensive and invasive (assessment of bladder function; inspection of the bladder’s lining). We hope that the means to more easily monitor bladder health will enable appropriate treatment at an earlier stage thus reducing the impact of bladder diseases on the many millions of sufferers.