The Institute of Pharmaceutical Science (IPS) is concerned with gaining a detailed understanding of human disease and employing this knowledge to discover, design, develop and ultimately deliver drugs to the patient with a view to improving the management of disease. There is also a strong interest in the appropriate use of medicines. IPS is one of the largest Research Divisions in the health schools and is organised in five groups: Chemical Biology, Drug Delivery, Pharmacology and Therapeutics, Pharmaceutical Biophysics, and Clinical Practice and Medication Use. There is a vibrant PhD programme with more than 90 students.
In the 2008 Research Assessment Exercise, based on the research volume metric, the Institute ranked 5th out of 25 Pharmacy Departments in the U.K. Particular areas of research strength include expertise in Systems Biology, Molecular Biophysics, Medicinal Chemistry and Metal Biology.
IPS has strong links with many of the other research divisions at King’s College London and consequently has developed a critically-important central role in the total research effort of the College. Staff have a substantial number of collaborations at a local, national and international level. Following the accreditation of King’s Health Partners, Academic Health Sciences Centre, the Institute joined three NHS trust pharmacy departments (Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts) and the Guy’s Drug Research Unit (Quintiles) to form the Pharmaceutical Sciences Clinical Academic Grouping. The aim is to cement the collaboration between staff in the Institute and the NHS Trusts and achieve excellence in service provision, in research, and in education and training.
1. The function of the molecular chaperone Hsp90
Heat shock protein 90 (Hsp90) is an ATP dependant molecular chaperone essential for both creating and maintaining the active conformation of key regulatory proteins, such as certain hormone receptors, mitogen activated protein kinases and tumour suppressors such as p53 and Rb. In order to achieve its function, Hsp90 acts as the centre of a multi-protein chaperosome complex that includes an array of co-chaperones. The chaperosome complex has been highly conserved throughout the eukaryotic lineage, and we exploit yeast as a genetically tractable model system in which to investigate the contribution made by each co-chaperone to the overall function of the chaperosome. For example, we can assess activity of Hsp90 substrates - such as the glucocorticoid receptor and the pp60v-src oncogernic kinase - in genetic backgrounds deleted for the genes encoding the co-chaperones.
2. The role played by the Smc5/6 complex in maintenance of genome integrity
There are three Structural Maintenance of Chromosomes complexes. The core of all three is composed of a heterodimer. One complex, cohesin (Smc1/3), keeps sister chromatids together prior to mitosis. Condensin (Smc2/4), is responsible for the chromosome condensation that occurs during mitosis. The third, Smc5/6, has an essential yet poorly characterised role. We are trying to understand the role played by this complex in maintaining genome integrity. Smc5/6 is found in a complex containing at least five other proteins, Nse1-5 (Non Smc Elements). We are generating mutant alleles of the corresponding genes, in order to observe how they disturb genome structure, thereby generating insight into the function of the Smc5/6 complex itself.
3. Conditional mutants in QRI2/NSE4 arrest at the G2/M transition
Cells deleted for NSE4 bearing a vector-borne wild type allele (W+), or the nse4-4ts allele, were grown at 250C and shifted to 370C for 4 hours. Cells were fixed, followed by staining DNA and spindles with DAPI (B), and anti-tubulin (C), respectively. Panels A (phase), B & C are cells from the same field of view.
BV vectors as potential gene delivery vehicles
BV is an insect virus that has been exploited over many years to direct expression of foreign proteins in insect cell cultures. Because the range of post-translational modifications, e.g. glycosylation, mediated by insects are, in comparison to bacteria or yeast, more similar to those of mammalian cells the baculovirus expression vector system (BEVS) has gained considerable popularity. BV can also transduce and deliver a functional gene to the nuclei of a range of mammalian cells often with efficiencies >90%. The list of non-host cells transduced successfully has grown in recent years and includes several examples of human primary cells, e.g., hepatocytes, neural cells and pancreatic islet cells. BV exhibits several features that make it attractive as a vehicle for in vitro gene delivery to mammalian cells and as a potential alternative to more traditional viral vectors for in vivo gene therapy. The Chemical Biology group are modifying the genome of BV with the aim of developing it as a therapeutically viable gene therapy vector. In particular the interest is in targeting baculovirus to specific cell populations in the liver that regulate the extra-cellular matrix remodeling that is critical in the pathogenesis of cirrhosis. The lack of any effective small molecule anti-fibrotic drug class represents a critical and pressing unmet clinical need for this disease and we hope to develop alternative therapeutic strategies based on BV gene therapy.
Recombineering reporter fusions
In collaboration with the Hope lab (http://bgypc059.leeds.ac.uk/~web/), we have developed a strategy, based on recombineering with a counter-selection cassette, to directly, and seamlessly, modify genomic fosmid clones to generate fusion reporters for analyzing gene expression in C. elegans. The method was described in Dolphin CT, Hope IA. (2006). Further information, including a FAQs page, on the group recombineering protocol can be found here.
Gene targeting in C. elegans
Since its adoption as a genetically tractable model animal the nematode C. elegans has provided invaluable, detailed insight into numerous fundamental biochemical processes. Many of these discoveries were and are still made using classical forward "phenotype-to-gene" genetic screens. However, in contrast to several other models, such as mouse and yeast, it has not yet proved possible in C. elegans to generate precise sequence changes at genomic loci via homologous recombination (HR). Thus, a robust and facile gene-targeting (GT) method remains a highly desirable and sought-after functional genomics tool for worm researchers. The group is hoping to develop a new approach for GT in C. elegans based upon HR mediated by bacteriophage recombinases.
Dr Mountford has divided his time between two distinct areas of research.
Firstly, the development of new synthetic methods for the preparation of classes of molecule that are either poorly described in the literature or are currently not described. The rationale behind targeting these classes of compounds lies in both an ability to construct compounds to probe regions of a drug target’s active site that are currently inaccessible using the constructs currently available, and the improved IP position that would be obtained if these molecules were incorporated into a drug candidate.
The second area of research lies in the application of Drug Discovery methods to biological targets. Current targets lie in the fields of allergy, pain and inflammation, areas which Dr Mountford knows well from his time at CBT.
Current research is focused on a number of biological targets, both those that are well described in the literature and also potentially new drug targets arising from original research being carried out at King’s College London.
Currently specific areas of interest are in:
Novel piperidine architectures
Synthesis of antimalarial Natural Products
Novel multi-component reactions
Evaluation of possible new approaches to organocatalysis
Fragment based Drug Discovery
Drug targets for Asthma, inflammation and pain.
Prof David Thurston's research interests include the discovery of sequence-selective DNA-interactive agents as anticancer drugs, antibacterial agent, and as transcription factor inhibitors.
He is also interested in the discovery of novel protein-protein interaction inhibitors as anticancer agents, the development of novel bio-analytical methodologies, and the application of pharmacogenomics and personalised medicine approaches to anticancer drug discovery and the practise of pharmacy.
His research has been funded from a variety of sources including the Research Councils, Cancer Research UK, the British Council, the Commonwealth Fund and various pharmaceutical companies. In 1996 his funding from Cancer Research UK was awarded Programme Grant status.
Dr Wagner's main research interests are in medicinal chemistry and chemical biology – developing chemical tools to address biological and biomedical problems. Research in his laboratory sits at the interface of chemistry and biology and research projects in his group - such as the development of inhibitors and assays for therapeutically relevant enzymes - are generally very interdisciplinary. Dr Wagner and his group use a range of different methods, from organic synthesis, through protein biochemistry to various analytical techniques, particularly fluorimetry. The Wagner group collaborates extensively with external partners in the UK, Denmark and Germany.
Current projects:
Glycosyltrasferases as drug targets
Glycosyltransferases (GTs) are enzymes that catalyse the transfer of a monosaccharide from a glycosyl donor to a suitable acceptor, e.g. a glycan, peptide or lipid (see e.g. Annu. Rev. Biochem. 2008, 77, 521-555). GTs play a key role in many biological processes underpinning human health and disease, including glycoprotein and cell wall biosynthesis in human pathogens, carcinogenesis, and cellular adhesion. Individual GTs represent promising therapeutic targets, and the Wagner group is developing small molecular GT inhibitors as lead compounds for drug discovery, and as chemical tools for the investigation of glycosylation networks in living systems (Nat. Chem. Biol. 2010, 6, 321-323.)
Synthetic modifications of biomolecules in aqueous solution
Dr Wagner and his group have developed synthetic methodology for the direct structural modification of sensitive biomolecules in aqueous media, obviating the need for protecting groups and for lengthy synthetic sequences. The group has particular expertise in the Pd-catalysed cross-coupling of nucleosides, nucleotides, sugar-nucleotides and amino acids. This synthetic approach has proved very useful for the generation of novel fluorescent bioprobes.
Chemical tools for NAD-dependent enzymes
The dinucleotide NAD (nicotinamide adenine dinucleotide) is required as a cofactor not only by redox enzymes, but also by other enzyme classes which use NAD for covalent modifications. Many of these enzymes, such as the PARP enzymes, the sirtuins, and NAD-dependent ligases, play essential roles in cell signalling and transcription, and are exciting molecular targets for chemical biology and drug discovery. Dr Wagner and his group are currently developing structural analogues of NAD for the selective inhibition of individual enzymes and for the real-time imaging of their activity, e.g. in living cells.
Dr Thanou and her group prepare fluorescent nanoparticles and study their diffusion in biological samples using Multiple particle Tracking and fluorescent microscopy
Engineering targeted nanoparticles for cancer siRNA delivery
Dr Thanou and her group have developed a novel ligand for breast and prostate cancer that can functionally deliver siRNA to tumours. They studied and optimised the organisation of this ligand on the surface of Nanoparticles for optimum receptor recognition and endocytosis.
Developing Carbon Nanopipes as drug delivery systems
Dr Thanou and her group are developing novel carbon architectures that can be used safely for biomedical applications. These architectures show chemical versatility and the potential to be used in Drug Delivery.
Dr Rahman's research activities focus on the application of synthetic medicinal chemistry and chemical biology techniques to the design, synthesis and evaluation of novel anticancer and antibacterial agents, along with studies to understand their molecular and cellular mechanisms of action. The key research areas are -
Development of Novel Telomerase Inhibitors:
Inhibition of telomerase can force tumour cells to enter replicative senescence leading to programmed cell death or apoptosis. Research in this area will target telomerase using a small-molecule strategy by interfering with i) Telomeric G-quadruplex structure, and ii) DNA/RNA hybrid structures that are formed during the catalytic cycle of telomerase. Formation of this unique heteroduplex is a key step in the catalytic cycle of telomerase in its processing to extend the telomere. Small molecules that bind to this duplex may inhibit telomerase by either stabilizing the structure and preventing strand dissociation, or by sufficiently distorting the substrate duplex to cause misalignment of key catalytic groups
Discovery of Novel G-Quadruplex Targeting Agents to Modulate Expression of c-Myc, c-Kit and K-ras Oncogenes:
Oncogenic transcription factors are an increasingly important target for anticancer therapies, as inhibition could allow the “reprogramming” of tumour cells, leading to apoptosis or differentiation from the malignant phenotype. For example, the c-Myc transcription factor plays a key role in the progression of most human tumours, and is over-expressed in a wide variety of human cancers. The proto-oncogene c-Kit codes for a 145-160 kDa tyrosine kinase receptor which regulates several important signal transduction cascades that control cell growth and the proliferation of cancer cells. Similarly, mutation and over-expression of the K-ras oncogene is strongly associated with pancreatic cancer. Promoters of all three oncogenes (c-Myc, c-Kit and K-ras) contain sequences that have been shown to form G-quadruplex structures that control their transcriptional activity. Research in this area is focused on targeting these G-quadruplexes with small molecules in an attempt to modulate transcription.
Development of Novel Bio-Analytical Methodologies:
Research in this area has led to development of a number of novel analytical methodologies to evaluate the DNA interactions of sequence-selective molecules. One particular area of success has been the development of a HPLC-MS assay that has been used to measure the kinetics of reaction of novel agents with DNA, and to evaluate their sequence selectivity. The group is working to develop the scope of these assays to allow the monitoring of drug-genomic DNA interactions in cells, and to study the interactions of DNA-binding drugs with mitochondrial DNA.
Discovery of Novel DNA-Interactive Transcription Factor Inhibitors:
A combination of traditional synthetic chemistry and automated techniques is used to discover novel gene targeting agents capable of recognising specific gene sequences and inhibiting transcription factor binding in a selective manner. Work on C8-linked PBD conjugates have shown selective NFkB transcription factor inhibiting properties, and significant activity against breast and pancreatic cancer and leukaemia both in vitro and in vivo.
Discovery of Novel DNA-Interactive Antibiotics:
This research area involves the design, synthesis and evaluation of novel sequence-selective DNA-interactive agents as antibacterials, targeted toward specific sequences of DNA in the bacterial genome with a focus on MRSA, VRE and mycobacterium.
Professor Peter Hylands has many years experience in natural product research and development, with an emphasis on the isolation and structural determination of novel bioactive compounds, both in academia and industry.
Professor Hylands has led multidisciplinary research programmes in Europe, the Americas and various Asian countries and has been an invited speaker all over the world. Important aspects of his present research are innovative chemometric metabonomic approaches to natural product research, notably the standardisation of plant extracts.
The research undertaken by Professor Davies represents two key themes – clinical and educational research.
The clinical research programme focuses on the critically ill and addresses problems experienced in the day to day clinical environment. For example, research investigating the use of midazolam (a sedative) on the intensive care unit, Guy's and St Thomas' NHS Foundation Trust, led to a change in prescribing policy, an achievement recognised nationally (UKCPA Advanced Practice Award 2006).
Other work, also undertaken at Guy's and St Thomas', evaluated the effectivness of clonidine, when given orally, as a sedative for children on the paediatric intensive care unit. Professor Davies has also studied the clearance of a number of drugs (morphine, quinine and cifpirome) by continuous renal replacements, to provide dosing guidance for prescribers.
The educational research programme focuses on the design and testing of pharmacist development frameworks as a direct response to the Clinical Governance agenda within the NHS, thereby improving the safe and effective use of medicines. Professor Davies is a founder member of the Competency Development and Evaluation Group (CoDEG, http://www.codeg.org) a collaborative network of specialist NHS practitioners and academics drawn from the two London Schools of Pharmacy.
These frameworks have been formally recognized by the Department of Health, in the policy document "Guidance for the Development of Consultant Pharmacist Posts" (DH March 2005) and have international application as demonstrated by their formal adoption in Australia to deliver recommendations outlined in the Australian Pharmaceutical Advisory Council (APAC) principles and Society of Hospital Pharmacists of Australia (SHPA) Standards of Practice for Clinical Pharmacy.
This research has directly led to a fundamental reform of postregistration pharmacist education which has seen the establishment of a collaborative between 6 Schools of Pharmacy (Brighton, East Anglia, London {2 Schools}, Portsmouth & Medway) and the National Health Service (www.postgraduatepharmacy.org ).
This initiative has been supported by a £1.3 million grant (Lead centre, University of London) secured from the Strategic Development Fund (HEFCE) in January 2007.
Kim’s main research interest is concerned with pharmacological aspects of addiction. She has explored the pharmacokinetics of the opioid agonist methadone in heroin dependent addicts including those who have become pregnant whilst prescribed the drug. A particular interest is in the effects of methadone in pregnancy and she is currently involved in a study to explore ventilator responsiveness, chemoreceptor sensitivity and arousals in infants exposed to methadone in utero in collaboration with Professor Greenough and colleagues in the School of Medicine.
Her research portfolio also includes investigation of the physiological effects of 3, 4-methylenedioxymethamphetamine (MDMA) use in a clubbing environment, in particular ecstasy-induced changes in water homeostatic measures. Individual differences in the metabolism of MDMA (CYP2D6 metaboliser status) and COMT rs4680 genotype have been shown to have an influence on various physiological phenotypes. Details about this and other current projects in the group can be found on the “Research” page (see links at the bottom of this page). Kim has several PhD students in her group working on substance misuse in pregnancy (Mei Wang FT 2011-2014; Dr Anna Vella PT 2010-2016); pharmacokinetics (Basma Alharthy FT 2010-2013) and ecstasy (Mario Misfud PT, 2006-2012) and is always looking to recruit enthusiastic research scientists to her group.
Development of Cultural Awareness and Sensitivity amongst Healthcare
Professionals, academic staff and students to enhance patient-centred care
sing the techniques of Motivational Interviewing (MI) to enhance student learning
Developing a portfolio-based approach to encourage continuing professional development (CPD) in undergraduate pharmacy students
Using a 'communities of practice' approach to coaching and mentoring community pharmacists in developing their CPD
Developing evaluation methods for curriculum review
Developing educational and practice supervisors (DEPS) in the pharmacy workplace
Using peer-assessment as a tool to promote student learning and reduce the burden of summative assessment
Dr Auyeung current research aims to examine patient satisfaction with information about medicines and to explore differences in the way healthcare professionals perceive what aspects of medicine information are important. This work is in collaboration with the Pharmacy Department at St Thomas’ and the Health Psychology Section at the Institute of Psychiatry.
She continues to deliver group sessions on ‘Thinking Patterns’ on the Post-polio Rehabilitation Programme run by the Lane-Fox Unit at St Thomas’. These sessions illustrate how beliefs, in general and those specific to post-polio syndrome, are instrumental in promoting successful self-management of this chronic condition.
Research is focused on the development and biopharmaceutical application of respiratory and intestinal epithelial cell culture models. Drug permeability, metabolism and gene delivery are studied:
Research is focused on the development and biopharmaceutical application of respiratory and intestinal epithelial cell culture models. Drug permeability, metabolism and gene delivery are studied: enhancement of drug transport presystemic drug metabolism epithelial pathology / toxicity
Inhaled Drug Delivery
"Inhalation biopharmaceutics" encompasses anything that may affect the rate or extent of drug absorption from the lung. Research projects in this emerging field include:
Dissolution in lung fluid Mucociliary and macrophage interactions Drug metabolism Epithelial permeability Toxicity of delivery vehicles (excipients, nanoparticles)
All these events occur at (or in) the respiratory epithelium.
Oral Drug Delivery
Current projects investigate interactions between intestinal fluid, the intestinal epithelium, orally administered drugs and formulation excipients.
Clinical Pharmaceutics
Projects with innovation aimed at improving practice in the manufacturing of pharmaceutical products.
Much of the research within the Drug Delivery group is focused on the analysis of human-associated microbes. The aim of this work is to better characterise these microbes in both health and disease.
The human lung and gut have been areas of particular importance. Most of work to date has focused on infections of the lungs of cystic fibrosis (CF) patients. It is particularly important to understand these infections given the mortality associated with respiratory failure within this patient group. Work to date has shown that a wide range of bacterial species are present and active in the CF lung. Moreover, many species that require anaerobic conditions for growth have been detected amongst a range of bacterial species not previously associated with the CF lung.
These studies are continuing – looking now at, amongst other aspects, the function of these bacteria in lung disease. Other respiratory conditions are also important. The Drug Delivery group also study the bacteria that are associated with the human gut mucosa in health and disease. These studies have shown that the bacteria associated with the gut mucosa of healthy individuals are quite distinct between individuals, yet are similar along the tract within an individual. This work is extending to study the gut in disease such as Crohn's disease and ulcerative colitis.
The Drug Delivery group work extends beyond these areas. Group members are also working on models of community development, interactions between microbe and human cells, improving and assessing therapies and their delivery. Other group members are studying the interface between environments and humans. This focuses on issues of spatial scale and incorporates aspects of stress e.g. pollutants and other chemical agents on populations and communities. This work needs the involvement of other scientists and clinicians. The Drug Delivery group is very fortunate to have the active support of such groups in the UK (currently mainly Southampton, London, Belfast and Liverpool) and abroad (USA and Australia).
The focus is to move from characterisation of what microbes are present, to develop a better understanding of the function of these microbes. From this improved understanding, similar improvements may follow in the longer term in terms of the treatment of infection.
Dr Al-Jamal has developed an extensive experience in designing and developing novel nanoscale delivery systems including dendrimers, liposomes, quantum Dots (QDs), viral vectors and chemically functionalised carbon nanotubes. Her current work involves pre-clinical translation of novel nanomaterials designed specifically for drug, siRNA, plasmid and radionuclide delivery for therapeutic or diagnostic applications. She reported for the first time the intrinsic anti-angiogenic activity of cationic poly-L-lysine dendrimers, and pioneered surface engineering of carbon nanotube-based vectors to deliver siRNA materials to the central nervous system (CNS) and solid tumours in vivo.
Current research interests:
Synthesis and characterisation of novel nanomaterials
Nanomedicine
Theranostic applications
Pharmacokinetic studies
Live small animal imaging by SPECT/CT and MRI imaging
RNAi
Gene delivery
Magnetic drug targeting
Stem cell research
Drug delivery to the BBB
Multicellular tumour spheroid cultures
Solid and metastatic tumour models.
Professor Martini's research interests include the use of ultrasonic processing technology to fabricate medical devices and pharmaceutical dosage forms, the design of dosage form concepts for delivering personalised medicines and developing drug delivery systems. Professor Martini has interests in developing closer links with Industry and with mechanisms for improving Open Innovation
Dr Dreiss' research focuses on characterising and understanding self-assembly processes in a range of polymeric and colloidal systems. Self-organisation driven by electrostatic interactions, hydrogen bonds or hydrophobic interactions is ubiquitous in nature and determines the mechanical and functional properties of materials. Projects in Dr Dreiss group, aim at understanding the principles of this self-organisation and building-up relationships between structure on the nanoscale and the macroscopic properties which result from it, such as rheology.
Small-angle neutron and X-ray scattering are used to probe the structure of systems of interest, covering a wide range of length scales down to the angstrom-size. The method of contrast-variation (with neutrons), which uses selective deuteration, offers the unique possibility of alternately hiding or highlighting constituents of interest, a key-attribute in these complex multi-component systems.
Current projects and systems of interest include:
Wormlike micelles formed in mixtures of surfactants; effect of oil encapsulation and additives; interaction with hydrophobically modified biopolymers;
Polymeric micelles and their potential as drug carriers; change in aggregates structure in the presence of drug; effect of pH and temperature; complexation with cyclodextrin and competitive interactions;
Oligomerisation and fibrillation of amyloidogenic proteins and peptides: structure, kinetic pathway and mechanism of formation
Biopolymers gels from gelatin and mixtures with natural polymers; competition between physical and chemical gelation (enzymatic crosslinking); applications in tissue engineering
Dr Barlow research over recent years has been primarily concerned with structural and computational studies of drugs, and drug and gene delivery systems. These studies have included: detailed characterisation of the molecular architectures and membrane interactions of gene delivery vehicles; development of novel software for modelling biological membrane structure; development of expert systems approaches for drug discovery and modelling of drug delivery systems; and the development of novel systems for heterologous expression of eukaryotic integral membrane proteins.
Topics:
Bio-informatics and chemo-informatics of Traditional Chinese Medicines;
gene therapy of mitochondrial disorders;
neutron reflectivity and SANS studies of drug delivery systems and model membranes.
The goal of Dr Mason's research is to understand how the dynamic composition of biological membranes influences how organisms respond to their environments. In particular, we are interested in how they interact with molecules designed to disrupt, disorder and/or cross their membranes.
Our approach is to obtain a fundamental, molecular level understanding of the effect of peptides or other drugs on the structure, organisation and dynamics of model membranes designed to closely mimic the properties of key target membranes in nature. This information is then put into context by relating the observed behaviour of these compounds in living cells to their biophysical features. In this way we are beginning to understand the role that biological membranes play in diverse areas including bacterial and malarial infections, genetic diseases and cancer metastasis.
Understanding the interactions of peptides with membranes at the molecular level allows us to modulate the activity of the peptide, leading to enhanced activity and reduced cellular toxicity. Membrane active peptides can have a variety of roles but we are particularly interested in peptides that have antibiotic properties or can be used as vectors for nucleic acids to deliver gene therapeutics to mammalian cells. By studying natural and designed antibiotic peptides we aim to obtain rules for the rational design of antibiotics that are active against bacteria such as Pseudomonas aeruginosa, fungi and the malaria parasite Plasmodium falciparum. Histidine rich amphipathic peptides can also be highly efficient gene or siRNA delivery vehicles. We have shown that such peptides are more efficient vectors when they can interact with negatively charged lipids in the target cell membrane. We aim to understand this interaction in more detail so that it can be exploited for biotechnological or therapeutic applications.The research uses a wide range of biophysical methods in conjunction with in silico molecular dynamics simulations which provide data which we incorporate in an overall view, together with in vitro activity assays, transcript and metabolomic profiling of how both bacteria and host cells respond to being challenged by the peptides.
Specific research themes include:
- Application of solid-state NMR methodologies to peptide structure and membrane dynamics
- Quantification of peptide secondary structure in membrane environments using Circular Dichroism (CD) and other optical spectroscopy methods
- The role of conformational flexibility in the mechanism of action and toxicity of cationic alpha-helical amphipathic antimicrobials
- The role of membrane interactions in the activity of human beta defensin-2 (hBD-2)
- Manipulating peptide-membrane interactions to enhance peptide mediated nucleic acid delivery and develop safe and efficient non-viral vectors
- Linking the biophysical activities of antimicrobial peptides to a molecular genetic view of challenged bacteria and P. falciparum
- Linking biophysical measurements to predictive in silico molecular dynamics simulations
- Development of Magic Angle Spinning (MAS) NMR approaches to metabolomic profiling
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.
Dr Preston's research interests centre around physiology of ageing of cerebrospinal fluid (CSF) dynamics and blood-brain barrier. Her research group has 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.
Dr Preston's group has 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.
Miles is internationally recognised for his work in cell signalling. He is particularly interested in understanding how the functioning of cyclic nucleotide signalling networks are regulated by spatial constraints and cross-talk (see Trends in Biochemical Sciences 35 (2010) 91-100; PMID: 19864144). He developed the now well-accepted concept that cAMP degradation by PDE4 phosphodiesterase isoforms targeted to specific signalling complexes and intracellular locales underpin compartmentalised cAMP signalling. The current focus of his work is in translating novel scientific discoveries concerning cell signalling systems into potential therapies and diagnostics for diseases such as chronic obstructive pulmonary disease (COPD), cancer, depression and schizophrenia.
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.
An alteration in the character and function of platelets is manifested in patients with inflammatory diseases, and these alterations are dissociated from the well-characterized involvement of platelets in thrombosis and haemostasis. Recent evidence reveals platelet activation is sometimes critical in the development of the inflammatory response. Understanding how platelets are activated during inflammation is therefore of fundamental importance. However, the mechanisms by which platelets participate in inflammation are diverse, and offer numerous opportunities for future drug intervention that are currently lacking with established anti-platelet drugs developed for inhibiting platelet aggregation.
We have previously shown the importance of platelets in orchestrating both acute and chronic inflammatory events of the airways, collaborating closely with Prof. Paolo Gresele (University of Perugia, Italy). We have reported that platelets direct leukocyte recruitment to areas of inflammation in allergic and non-allergic models of inflammation via various selectin adhesion molecule interactions. These interactions create platelet-leukocyte complexes during rheological events that ‘prime’ subsequent leukocyte adhesion to inflamed endothelium. I am currently investigating how platelet activation occurs during these non-thrombotic settings.
We also study the role of platelets in airway remodelling events in models of chronic allergic inflammation, and have reported a requirement for platelets for events such as smooth muscle thickening, epithelial hyperplasia, and collagen deposition. Current dogma would suggest that platelet participation in tissue damage and influencing repair processes is indirect and secondary to their affects on leukocyte recruitment. However, we have shown that platelets have the ability to migrate through inflamed tissue. We continue to research this intriguing and novel aspect of platelet function, since platelets contain a formidable array of inflammatory mediators and cytotoxic compounds within their granules that are capable of inducing tissue damage and subsequent repair processes directly.
An additional major interest of mine is the mechanisms that govern leukocyte and stem cell mobilization from the bone marrow. With Dr. Sara Rankin (Imperial College, UK), I revealed that differential mobilization of progenitor cell subsets (e.g Haematopoietic progenitor cells, endothelial progenitor cells, and mesenchymal stem cells) is dependent upon the cytokine milieu that regulates cell retention and proliferation within the bone marrow. I am currently interested in the role of platelets in stem cell recruitment, and mechanisms of platelet production from bone marrow megakaryocytes during disease.
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I joined King's to study for a PhD in analytical chemistry. Foreseeing a future in industry, I wanted a programme of study that would equip me with skills that are required not only in the laboratory but also day to day life. Being part of the Forensic Science and Drug Monitoring Research Division (incorporating the world renowned Drug Control Centre) has provided me with some fantastic opportunities to enhance and develop these skills, opening up a variety of career opportunities.
I have been interested in pharmaceutical research since undergraduate studies. So after obtaining my master's degree in China and feeling confident in myself, I have been determined to pursue my PhD study at King's. I thought the professors here make a great contribution to pharmaceutical sciences before I came - now this has been proven by the reality. I am very lucky that I have become a student at King's and sponsored by King's (KORS). During this process, the staff from here have helped me a lot and it makes everything go well. I should say thanks to them.
I am very happy that I am learning at King's. King's is very student-oriented. They help you resolve all the problems and make your life and study here not be disturbed. King's is a big family and I can make contact with students from all over the world. I enjoy the good relationship between my supervisor and me. She is kind and responsible and leads me to a higher research point. But it would not work if there were not such a good research setting at King's.
One more thing I have to mention is that once studying in London you will enjoy a different social life, seeing political figures, singers and royal members, visiting museums, galleries, concert halls, taking part in parties, parades, Olympic torch relay, raising money for charities and all kinds of volunteer work. You will benefit from not only studying at King's but also living in London. Once you have been here, you will never be ready to leave.