Pharmacology & Therapeutics
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Blood Brain Barrier Group
Research by this group, comprising Dr David Begley, Dr Jane Preston and Dr Sarah Thomas, centres on understanding the physiology and pathophysiology of barrier layers which limit and regulate molecular exchange at the interfaces between the blood and the neural tissue or its fluid spaces. Quantification and characterisation of brain and CSF delivery of drugs in health and disease forms a significant part of the studies that are undertaken. Understanding of compound delivery includes study of the generation and flow of brain interstitial fluid, in vivo transport kinetics of a library of compounds to formulate predictive rules for brain entry, chemical modification of iron chelators to improve CNS delivery, distribution characterisation of all licensed HIV reverse transcriptase inhibitors and major HIV protease inhibitors to systematically identify single and combined drug optimisation. CNS delivery strategies employing vectors such as liposomes, nanoparticles and specific protein (amino acid) sequences are also an interest. Pathophysiological models include barrier breakdown and modulation in multiple sclerosis, barrier changes and neuropathy seen in lysosomal storage diseases, brain entry of drugs to treat African trypanosomiasis, the effects of antidepressants on glucocorticoid entry to brain, and age-related studies on CSF turnover, with retention of amyloid-beta and proteomics identification of biomarkers relevant to late life neurodegeneration.
Neurodegenerative diseases
Professor Peter Jenner and Dr Sarah Salvage head a team of scientists investigating the cause, treatment and cure of Parkinson\'s disease. The group utilises a range of behavioural, biochemical, immunocytochemical and in situ hybridisation techniques in the study of neurodegenerative disease. Current interests centre on the role of proteasomal function in cell death in Parkinson\'s disease, the use of non dopaminergic approaches to the treatment of the symptoms of Parkinson\'s disease and the development of neuroprotective approaches to the treatment of the illness that will slow or stop disease progression. Professor Jenner has formed a development spin-out company, Proximagen, specifically for the development of new treatments for neurodegenerative diseases.
Pulmonary pharmacology
The Sackler Institute of Pulmonary Pharmacology was established in 1993 to provide multidisciplinary research to investigate the mechanisms and pharmacological basis of respiratory diseases. The Institute also has good collaborative links with clinicians in the School of Medicine that allows translational research to be undertaken in patients with respiratory diseases like asthma and chronic obstructive pulmonary disease. Professor Clive Page, Dr Domenico Spina, Dr Simon Pitchford and Dr Ian McFadzean have developed and utilise a number of models to further our understanding of the pathogenesis and treatment of lung disease. Research areas include the cell and molecular basis of inflammatory cell recruitment, airway remodelling and airway hyperresponsiveness. The use of cell based assays, in vitro organ bath studies and in vivo models of characteristic features of pulmonary disease allow us to probe the mechanism of a variety of intracellular signalling pathways, receptors, adhesion molecules, inflammatory mediators and cells in these processes. Dr Ian McFadzean brings expertise in isolated cell recording techniques and calcium imaging to further strengthen and enhance our research interest in the role of sensory nerves in airway irritability.
Vascular biology and inflammation Group
Research by this group, comprising Dr Julie Keeble and Dr Manasi Nandi, focuses on the biological systems underlying vascular physiology and pathophysiology in inflammatory and related disorders, including sepsis, arthritis and thermoregulatory dysfunction. Both researchers are members of The Centre for Integrative Biomedicine and are involved in actively facilitating the development and training of integrative techniques for biomedical research, in line with the 3R\'s. In particular these groups utilise Radiotelemetry (for conscious blood pressure, temperature and activity monitoring), Laser Doppler Imagery (microcirculatory blood flow), Echocardiography (cardiac function) and various techniques for investigating pain responses. Through the use of both genetic and pharmacological approaches, the biological significance of enzymes regulating nitric oxide bioavailability and the transient receptor potential receptor channels, are currently being investigated.
- Mechanisms of Inflammatory Cell Trafficking and airway remodelling
- Role of Phosphodiesterase in Airway Diseases
- Role of Airway Nerves in Lung Disease
- Mechanisms of Airway Hyperresponsiveness
- Mechanisms of Vascular Permeability
- Mechanisms of Equine Respiratory Diseases
- Pulmonary embolism
- Drug Delivery/ nanoparticles
Research in Dr Begley's laboratory is directed towards understanding the fundamental function of the BBB as a dynamic regulatory interface between the blood and brain but in addition we work closely with the pharmaceutical industry to develop strategies for dug delivery to the brain. In this They are examining the physico-chemical properties of molecules which will determine their passive or active movement across the endothelial cells of the BBB and exploring vector systems for the delivery of difficult or large "biopharmamaceuticals" such as growth factors, peptides/proteins and enzymes across the BBB.
They are also currently working on drug delivery to the CNS in lysosomal storage diseases. These are a group of approximately 50 inherited metabolic disorders many of which are neuronopathic and result in severe neurological decline and death in the first quartile of life. They result from an absent or reduced activity in one of a number of lysosomal degradative enzymes which results in the cellular accumulation of an intermediate storage product. In the past few years treatments have been devised which consist of enzyme replacement therapy (ERT) where genetically engineered functional enzyme is infused intravenously. This enzyme can be taken up by body cells and restore the functional defect.
Unfortunately the enzymes do not cross the BBB in therapeutic quantity, if at all, and the neurological damage persists and progresses. Other treatments consist of small molecular weight therapies, the so called substrate reduction therapies (SRT) and chemical chaperones which reduce storage product formation or boost enzyme activity. It is critical to the development of new effective CNS treatments to understand how current treatments interact with the BBB. There is also evidence that the BBB may be damaged in these conditions due to storage or associated inflammation thus contribution to the CNS damage.
The group is also researching the use of nanoparticles and similar systems as vectors for drug delivery to the CNS and have active collaborations with Universities and Research Institutes in Frankfurt, Moscow and Padua.
Dr Spina's research involves the pharmacology of respiratory disease and inflammation. Dr Spina is particularly interested in investigating the role that sensory nerves play in mediating irritable airways a condition which makes asthmatic subjects uniquely sensitive to their external environment. Moreover, he has interests in the mechanisms that give rise to cough and is studying the role of inflammation in these physiological situations. His in vivo expertise involves the use of cough and asthma models in rodents and guinea pigs to measure of respiratory lung mechanics, in vivo plethysmography, lung resistance and compliance, airway inflammation, and numerous in vitro techniques (e.g. organ bath measurements of isometric tension).
The common thread running through Dr McFadzean's research career has been an interest in the mechanisms by which neurotransmitters, and drugs regulate calcium entry into cells. During his PhD work he used electrophysiological techniques to study the mechanisms by which opioid receptor agonists inhibit synaptic transmission in the central nervous system, work which contributed to the development of the hypothesis that pre-synaptic opioid receptors inhibit neurotransmitter release by inhibiting calcium entry into nerve terminals through voltage-operated calcium channels. His interest in this area continued during my post-doctoral work at University College London where he used a neuroblastoma hybrid cell line as a model system, along with whole-cell patch-clamping techniques, to study the intracellular pathways that link receptor activation to inhibition of voltage-operated calcium channels. By injecting antibodies selective against different G-protein subtypes into the cells we were able to show that antibodies against the a-subunit of Go were able to prevent the inhibitory action of neurotransmitters on the calcium currents. This was one of the first demonstrations of this key signalling role for Go in neurones.
At King's College London he turned the focus of his research away from neurones and onto smooth muscle cells, but still retained his interest in calcium entry pathways. Again the approach was to develop a model system in which to study drug effects, in this case single smooth muscle cells isolated enzymatically from the anococcygeus muscles of mice. The mechanisms by which excitatory neurotransmitters produced contractions of this and other tonic smooth muscles muscle had not been fully elucidated, though evidence pointed to them increasing calcium entry via poorly defined pathways. In collaboration with Dr Alan Gibson at King's, he set out to identify the calcium entry pathway activated by contractile agonists and this work culminated with the identification of a store-operated calcium entry pathway that was activated following receptor mediated depletion of internal calcium stores (a process called capacitative calcium entry). This was achieved using a combination of whole-cell patch clamp to measure the small calcium entry current directly and Fura-2 microfluorimetry to monitor the consequential changes in intracellular calcium. Although up to that point store-operated calcium entry had been described in a variety of other cell types, this was arguably the first report of its electrophysiological characterisation in smooth muscle. Since then store-operated calcium entry has been shown to occur in a range of smooth muscles and drugs that inhibit the process have the potential to act as smooth muscle relaxants.
More recently Dr McFadzean's work has turned towards using electrophysiological and microfluorimetric techniques to study the pharmacology of airway disease. For example, in collaboration with Dr Dom Spina he has been developing projects to determine whether blockers of potassium ion channels might alter calcium entry into neutrophils. We are also studying the electrophysiology of sensory nerves involved in the cough response with a view to identifying novel targets for the development of antitussives, including pre-synaptic inhibitors of transmission in the afferent arm of the cough circuitry.
Research interests centre around physiology of ageing of cerebrospinal fluid (CSF) dynamics and blood-brain barrier. We have previously studied the role of ageing in CSF clearance of Amyloid-β (1-40) and the main findings indicated that with age, Aβ did not undergo the rapid removal from CSF seen in young animals, but was retained in CSF and brain (Preston 2001). In addition, the choroid plexuses forming the blood-CSF barrier avidly accumulated and degraded excess Ab in young animals, but the aged barrier was unable to increase degradation and showed down-regulation in mitochondrial activity suggestive of toxicity (Preston et al 2004). These studies led the research focus more generally toward ageing of the blood-CSF barrier, fundamental to the handling of a range of potential neurotoxins.
We have found age-related changes in CSF production and blood-CSF barrier function which would predispose to 'stagnation' of CSF and subsequent brain accumulation of any compound found in the fluid (Chen et al 2005, Neurobiol. Aging). There is also down-regulation of de novo protein synthesis by the choroid plexus, including reduced synthesis and CSF content of the protein transthyretin (Chen et al 2003, Chen et al 2005, J. Geront.), which is both a thyroxine binding protein, and also a chelator of Ab and prevents neurotoxicity. Ongoing research is using 2-D gel proteomics to identify biomarkers for ageing, e.g. ↓ transthyretin, which may increase risk of late life neurodegeneration (Preston et al 2004, Redzic et al 2005, Chen et al 2004). A second theme concerns poor early nutrition in utero, and risk of late life hypertension and diabetes using a rat model, funded by the British Heart Foundation.
Dr Keeble's research is concerned with links between sensory nerves and disease. Her current work is particularly focused on the role of the Transient Receptor Vanilloid 1 (TRPV1) receptor in joint disease.
TRPV1 is located on a subset of C-fibre and Aδ sensory neurons and is intrinsically associated with pain and inflammation. It is often considered an integrator of noxious stimuli, e.g. noxious heat (>43ºC) and extracellular protons (pH<6.0). Most people think they have never heard of TRPV1, but are actually acquainted with it without realising.
Capsaicin, the pungent component of hot chilli peppers, is the most recognised agonist of the TRPV1 receptor. Thus, when we eat a very hot curry, TRPV1 is responsible for the painful, burning sensation.
Intriguingly, Dr Keeble and her group have found that TRPV1 is pro-inflammatory or anti-inflammatory, depending on the disease, i.e. it is pro-inflammatory in arthritis but anti-inflammatory in sepsis.
They are currently trying to determine the mechanisms underlying the opposing effects of TRPV1.
Nitric oxide production can, however, under certain conditions also contribute to disease phenotype. The most striking example of this is septic shock, where exposure usually to a bacterial infection results in the expression of an inducible isoform of NOS (iNOS or NOS2) resulting in excessive and unregulated nitric oxide production. This excessive nitric oxide production contributes towards a precipitous fall in blood pressure observed in these patients. This in turn can lead to cardiovascular collapse, inadequate organ perfusion and multi organ dysfunction - a major cause of mortality throughout intensive care units worldwide.
The synthesis of nitric oxide by NOS requires a number of cofactors, one of which is tetrahydrobiopterin. Tetrahydrobiopterin (BH4) has been demonstrated to be an essential cofactor for all three isoforms of NOS. Therefore, changes in intracellular BH4 concentrations have the potential to modulate nitric oxide production and blood pressure. Pharmacological modulation of the biosynthetic pathway that regulates BH4 availability has potential therapeutic utility in a variety of cardiovascular disorders. By utilising pharmacological and genetic approaches, the significance of this pathway in normal physiology and pathophysiology is being investigated.
Mechanism of neurodegeneration and treatment of motor disability and drug-induced side effects in movement disorders, particularly Parkinson's Disease. Symptomatic treatment in Parkinson's disease
Parkinson's disease is one of the few neurodegenerative disorders where the symptoms are reasonable well treated, particularly early in the disease progression. However, there are a number of problems associated with the treatment of Parkinson's disease. Firstly long-term use of the existing treatments, for example levodopa, results in unpredictable responses to the drug, or the onset of abnormal involuntary movement (dyskinesia). Part of our research is investigating the cause of these side effects and finding better pharmacological agents to treat the motor symptoms, and to prevent or reduce dyskinesia. Secondly, the present treatments only treat the symptoms associated with movement, and do not address the other non-motor symptoms of the disease. We are investigating the pathology associated with these non-motor symptoms which include sleep disorders, autonomic dysfunction, anxiety, depression and pain, all of which significantly affect the patient's quality of life, with a view to understanding their cause and improving their treatment
Neuroprotection in Parkinson's disease
Although the symptoms of Parkinson's disease can be reasonably well controlled, the drugs do not slow or stop the progression of the disease. We are further investigating the mechanisms of cell death associated with Parkinson's disease including proteasomal dysfunction, autophagy and apoptotic cell death and searching for novel agents that are able to slow its progression. We are particularly interested in the neuroprotective role of an endogenous protein called osteopontin, inhibitors of nitric oxide synthase and histone deacetylase inhibitors
The main focus of Dr Thomas' laboratory is to investigate the ability of molecules to cross the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (choroid plexuses and arachnoid membrane) and reach the central nervous system (CNS) in health and disease. Dr Thomas and her group are especially interested in membrane transporters and the relationship between drug concentrations in the cerebrospinal fluid (CSF) and the brain tissue.
