Pharmaceutical Science (Institute of)

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MPhil/PhD

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Part Time, Full Time

Staff interests associated with the research programme and its research groups

The Chemical Biology Group comprises Professor David Thurston, Professor Peter Hylands, Dr Sukhi Bansal, Dr Colin Dolphin, Dr Cristina Legido-Quigley, Dr Paul Long, Dr David Mountford Dr Penka Nikolova, Dr Richard Parsons, Dr Barry Panaretou, Dr Khondaker Rahman, Dr Maya Thanou, Dr Gerd Wagner and Emeritus Professor Bob Hider. Research is aimed at elucidating and understanding molecular mechanisms of disease, especially in the areas of neurodegeneration, infection and inflammation. To aid and advance drug discovery in these areas, the group develops and applies novel chemical, analytical and biocomputational tools for the investigation of complex biological systems. The research interests of staff range from medicinal chemistry to cell biology. With this breadth of expertise, the group provides a unique environment for the highly interdisciplinary type of research that is a hallmark of modern Chemical Biology.


The Chemical Biology group brings together scientific expertise in a broad range of areas, from medicinal chemistry to cell biology:

Medicinal chemistry: the group takes a variety of approaches to access new areas of chemical space – from the rational design of small molecular probes and inhibitors for therapeutically-interesting targets (e.g., glycosyltransferases, immunoglobulin G) to novel approaches in natural product chemistry. Synthetically, the group has particular strengths in peptide, nucleotide, carbohydrate and heterocyclic chemistry, and in the chemical modification of nanoparticles for targeted drug delivery. It also has a strong interest in marine natural products, to explore the potential of natural products derived from marine symbiosis for drug discovery. Natural product chemistry is also represented by the development of novel analytical approaches to the standardisation of complex mixtures as in plant extracts, and also the use of informatics in drug discovery.

Bioinorganic chemistry: the group has a world-leading reputation for its contributions to the development of clinically-useful iron chelators. Deferiprone, the first orally-active iron chelator introduced into man, is already used worldwide for the treatment of iron overload.

Bioanalytical chemistry: the group is the home of one of the few international laboratories capable of the synthesis and quantitation of hepcidin, a master regulator of iron metabolism. The group also has expertise in the use of mass spectrometry and nuclear magnetic resonance spectroscopy for metabolomic studies.

Cell biology: the group has established models in several prokaryotic and eukaryotic organisms, including yeast and Caenorhabditis elegans for applications in Chemical Biology.


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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. FACS analysis reveals that cells.

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020 7848 4003
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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 it’s 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.

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020 7848 4806
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  • Metabonomics “The quantitative measurement of the multivariate metabolic responses of multicellular systems to pathophysiological stimuli or genetic modification”. (GLOBAL SYSTEM ANALYSIS) Nicholson et al, Xenobiotica 1999. In particular for application in toxicity, disease and nutrition.  
  • Fundamentals of liquid chromatography and applied liquid chromatography coupled to mass spectrometry (in particular micro and nano LC for high sensitive analysis of small molecules and peptides)  
  • Capillary Electrochromatography/Electrophoresis and applications.  
  • Ultra Performance liquid chromatography and applications.  
  • NMR analysis (1D, 2D and MAS) of biofluids and tissues.  
  • Advanced statistical analysis (chemometrics)  
  • Chromatographic methods to calculate phase-analyte interactions (frontal analysis approach)  
  • Molecularly imprinted polymers. MIPs  
  • Validation of analytical methods
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020 7848 4722
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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.
In addition to his research and teaching responsibilities within the School of Pharmacy, Dr Mountford is an Innovation Fellow, working with King’s College London Business Ltd. to promote the research being carried out in the Institute of Pharmaceutical Science, and to develop links between the Institute and Industry to better facilitate translation and partnering of projects.

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.

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020 7848 4840
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Prof David Thurston academic research interests include the discovery of sequence-selective DNA-interactive agents as anticancer drugs, antibacterial agents, 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. His laboratory has benefited from continuous Programme Grant support from Cancer Research UK between 1996 and 2013.

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0207 848 4279
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Understanding the diffusion of nanoparticles in biological samples

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.

Tel:
(0)20 7848 4807
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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.

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0207 848 6158
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Mechanisms and Process in Biochemical Adaptation

Using experimental and bioinformatics approaches, Dr Long’s research focuses on how biosynthetic pathways have evolved to generate the rich chemical diversity found within living cells. By studying biosynthesis at the molecular level in Streptomyces bacteria and during complex marine invertebrate-microbial symbioses, Dr Long hopes to gain insight into the chemical ecology of these compounds and to assess their potential for drug discovery.
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020 7848 4842
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  • Structure-function studies of the p53 family of transcription factors and their role in cancer and other human diseases
  • Protein stability, protein (mis)folding, aggregation and disease
  • Protein-protein, protein-DNA interactions.
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020 7848 4276
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Prof 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.

He 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

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020 7848 4387
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Dr Parsons' research focuses upon the role that toxicology has in pathogenic process in neurodegenerative disease, in particular the interplay between environmental exposure and genetic susceptibility.

Alzheimer's disease – the production of amyloid-ß by the sequential actions of ß- and ß-secretase, and its subsequent aggregation into senile plaques, is one of the hallmarks of Alzheimer’s disease (AD).

Dr Parsons' research has investigated how protein lipidation (palmitoylation and isoprenylation) regulates the protein:protein interactions between ß-secretase (BACE1) and other proteins involved in its subcellular trafficking. BACE1 undergoes highly-regulated subcellular trafficking within the cell, and within certain subcellular regions BACE1 associates with its substrate, APP, leading to cleavage and production of amyloid-ß.

Dr Parsons' research has shown that inhibition of these protein lipidation reactions results in altered subcellular trafficking and reduced amyloid-ß. In collaboration with colleagues from St. George's, University of London, he is currently investigating the role that protein isoprenylation has in the amyloid-ß-induced inflammatory response.

Parkinson's disease - dysfunctional energy metabolism is present in many neurodegenerative diseases, which arises from reduced Complex I activity. The highly oxidising environment within the dopaminergic neurones of the substantia nigra, the neurones which degenerate in Parkinson's, leaves them particularly susceptible to reduced Complex I activity.

Dr Parsons is interested into how N-methylation biotransformation of proneurotoxins is involved in the pathogenic process. His research has shown that the enzyme nicotinamide N-methyltransferase (NNMT), which converts nicotinamide (a form of vitamin B3) into 1-methylnicotinamide, is significantly higher in PD brain than in disease-control brain. This appears to be a neuroprotective response of the cell to the underlying pathogenic process, as 1-methylnicotinamde is neuroprotective towards dopaminergic neurones, increasing Complex I activity and stabilising its structure.

Also, overexpressing NNMT in a dopaminergic neuronal cell-line leads to increased cell viability and Complex I activity. In collaboration with colleagues both within the Division and at Imperial, the next stage in Dr Parsons' research is to design lead compounds which exploit this neuroprotective action of 1-methylnicotinamide, which may provide a viable therapeutic avenue for the treatment of PD.
Tel:
(0)20 7848 4048
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Design and synthesis of peptides, peptide mimetics, radiopharmaceuticals and polymers.

Other research interests:
  • Combinatorial chemistry
  • Anti-sense therapeutics
  • Biomimetic catalysis
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020 7848 4785
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This group, which comprises Professor Graham Davies, Dr Vivian Auyeung, Dr Sue Jones, Dr Jig Patel, Professor David Taylor, Dr Cate Whittlesea and Dr Kim Wolff, integrates clinical practice and medication-related research activity across King’s Health Partners, namely King’s College London and the local NHS Foundation Trusts, Guy’s and St Thomas’, King’s College Hospital, and South London and Maudsley. Research centres on a number of areas:

Medication Optimisation

  • Information about medicines and adherence: this work investigates the relationship between the information patients receive about their medicines and how they are used. This work will lead to the design and evaluation of more effective medicines support systems to improve informed patient adherence to their prescribed medicines.
  • Medication Safety: this work focuses on detecting and reporting medication safety incidents in order to design, implement and evaluate a range of interventions to reduce risk. The group currently collaborates on patient safety initiatives with colleagues at St James's Hospital and Trinity College Dublin on safety culture.

Clinical Research

  • Mental Health: this work explores the use of anti-psychotic and anti-depressant medicines to understand the influence of a range of factors on their clinical use. An important strand of this work is the study of the efficacy and safety of agents recently introduced to the market.
  • Critical Care: this work focuses on medicines use (mainly sedatives and antibiotics) in patients with sepsis and severe sepsis.
  • Other work supported by the Biomedical Research Centre under the supervision of Professor Davies evaluates the pharmacokinetic and pharmacodynamic properties of a low molecular weight heparin when prescribed during pregnancy.

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David Taylor is involved in research into the effects of drugs in all areas of psychiatric practice.
His name interests are in naturalistic outcome studies, prescribing practice and meta-analysis. He has published influential work on antipsychotics and diabetes, antipsychotics and weight changes, clozapine augmentation, race and prescribing practices, naturalistic outcome with risperidone long-acting injection, antidepressants in chronic physical illness and drug treatment of Generalised Anxiety Disorder.
He has published around 200 papers in peer-reviewed journals which together have been cited more than 3000 times. His H Index is 35”
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020 3228 5040
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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

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020 7848 4049
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Dr Patel’s research is concerned with the optimal use of anticoagulant therapy in clinical practice and primarily focuses on addressing anticoagulant drug dosing issues where uncertainties exist. This work involves pharmacokinetic modelling of the anticoagulants, including the novel oral anticoagulants.
Dr Patel’s is also interested in understanding the reasons underlying non-adherence to anticoagulant therapy, so that long-term outcomes for patients prescribed anticoagulants for stroke prevention and for the treatment of venous thromboembolism are improved. This research sees collaboration with Dr Vivian Auyeung, KCL.

At King’s College Hospital, Dr Patel continues to support pregnant women prescribed low molecular weight heparin in the thrombophilia clinic. In addition, Dr Patel is responsible for directing the King’s Anticoagulation Reference Centre: http://www.kingsthrombosiscentre.org.uk/index.php/anticoagulation

The King’s Anticoagulation Reference provides:
consultative advice on the optimal use of anticoagulant agents where uncertainty exist
template guidelines on anticoagulation therapy for others to adopt for local use
anticoagulant monitoring service of the novel oral anticoagulants
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+44 (0)207 848 4838
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Prof Weinman's research is concerned with the influence of psychological process on health, illness and health care delivery.
The main focus of this has been on the ways in which patients’ beliefs about their illness and treatment affect self-regulation and self-management across a wide range of major physical health problems.
Prof Weinman is particularly interested in understanding the reasons underlying non-adherence to treatment and in developing effective interventions for improving medicines use. This work has also resulted in the development of a number of widely used measures and cognitively-based interventions, which have been shown to be effective in improving adherence to treatment, recovery and quality of life.
Prof Weinman's research also focuses on the ways in which psychological factors such as stress, emotions and cognitions influence the process of recovery from major illnesses such as acute coronary syndrome and from invasive medical procedures such as surgery and intensive care.
More recently, this work has broadened to include the investigation of psychological aspects of wound healing and recovery. This has involved a range of studies, which have explored the complex relationship between psychological factors, particularly stress, and speed of wound healing. It includes both experimental and interventional studies, which have shown a consistently strong relation between stress and wound healing speed, and clinical studies which have assessed factors influencing speed of healing of chronic skin wounds, such as foot and leg ulcers, and recovery from post-operative wounds.
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020 7188 0180
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As an ‘Addiction Scientist’ Dr Wolff has led on the use of biomarkers of substance misuse in different populations (high risk drivers; smokers, clubbers and those receiving methadone treatment including pregnant women) to aid assessment by healthcare practitioners.
Her research has involved both laboratory research and studies ‘in-the-field’: applying the findings of investigative research to ‘point-of-care’ situations.
Her research team has carried out the collection of biological material from drug dependent patients to identify markers of substance misuse as follows: A pharmacokinetic study of methadone in pregnancy demonstrated increased clearance in the third trimester has led to recommendations of the need for methadone maintenance in pregnancy rather than reduction of methadone dosing; Her research has shown that the CDT concentrations in blood are superior for assessing high risk drink drivers compared to other biomarkers.
The findings have resulted in a change of national policy for the Driver Vehicle Licensing Agency (DVLA) who has made CDT the sole biomarker for use by medical practitioners to aid decision making with regard to relicensing high risk drink drivers; Using different biomarkers (vasopressin and oxytocin) her team has been able to demonstrate the adverse impact of ‘ecstasy’ (MDMA) use on water homeostasis: the first group to show MDMA driven oxytocin release in man (Wolff et al, 2006).
The ‘point-of-care’ message in this case was that clubbers should restrict ‘free water’ intake when consuming MDMA to avoid adverse effects, potentially water intoxication; Recent work using plasma cortisol concentration as an indirect biomarker of hypothalamic-pituitary-adrenal (HPA) axis functionality has shown that MDMA consumption can bring about HPA axis dysfunction (Wolff et al, 2012) and; further work has found that poor metaboliser status for enzymes CYP2D6 and COMT in MDMA users were found to be significantly linked to biochemical events that trigger neuroendocrine abnormality, water intoxication and HPA dysfunction in vulnerable individuals.

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020 7848 0441
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Dr Jones current research has a focus on improving the student experience to enhance their professional & personal development and CPD. Student groups include pharmacy undergraduates as well as a range of healthcare professional (HCP) academic and clinical staff working in King's Health Partner (KHP) organizations. This has arisen due, in part, to work with KLI on their MA in Clinical Pedagogy; a programme for HCP staff working in clinical practice. As a consequence, a number of research projects are in progress:

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

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020 7848 4847
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Dr Auyeung is a Health Psychologist with an interest in developing interventions to address issues around non-adherence to prescribed medicines.

She joined the Clinical Practice and Medication Use Group in May 2009. Her 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 Guys’ and St Thomas’ NHS Foundation Trust.

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.

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020 7848 4818
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The Drug Delivery Group comprises Dr Ben Forbes, Professor Gino Martini, Dr Khuloud Al-Jamal, Dr David Begley, Dr Ken Bruce, Dr Lea Ann Dailey, Dr Jane Preston, Dr Paul Royall, Dr Stuart Jones, Dr Sarah Thomas and Emeritus Professor Gary Martin. The Group undertakes research and development in pharmaceutical technology and applies scientific principles both in the formulation of medicines and in the development and use of predictive models of drug absorption. This involves not only some of the more challenging conventional drug molecules but also the products of biotechnology. The ability of a formulation to influence the site and duration of drug action and affect therapeutic success is the major theme and results in a multifaceted research programme.

A major focus of the group is respiratory delivery and provides an excellent example of the collaborative nature of the group’s research in that all members have expertise that contributes to inhaled drug delivery research. This expertise is combined to develop novel strategies for drug delivery by inhalation and the treatment of respiratory disease. Projects extend from the science of aerosol formulations from dry powder and pressurised inhaler devices to the biopharmaceutics of particle-cell interaction, including gene therapy, and the characterisation of bacteria in lung diseases such as cystic fibrosis.

Topical delivery is another area of strength and the group has state-of-the-art facilities to design, formulate and evaluate topical preparations. These are screened in vitro using human skin diffusion models and in vivo using healthy volunteers. A number of novel devices, formulations and analytical techniques have been developed within the group and are being evaluated for commercial potential. Research into oral delivery falls into two main categories: (i) the interaction between gastrointestinal factors with lipid formulations in the intestine, and (ii) novel formulations for the delivery of drugs to the colon.

The manufacture, characterisation and evalution of nanomedicines for both drug delivery and diagnostic purposes is a third major research theme within the Drug Delivery Group. Projects range from the evaluation of carbon nanotubes as drug carriers and imaging agents and the investigation of new polymeric materials for nanomedicine development through to the evaluation of nanomedicine safety and efficacy. Nanomedicine research within the Drug Delivery Group is highly interdisciplinary where strong collaborations both with other research divisions within King’s College London are vital, as well as numerous national and international partnerships.

A fourth are of research 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 and proteomics identification of biomarkers relevant to late life neurodegeneration.


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Dr Forbes' 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.
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020 7848 4823
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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.

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020 7848 4670
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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.
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Tel:
020 7848 4525
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Dr Dailey's research interests center around the field of pulmonary drug delivery. Specific areas include:
  • Development and characterisation of a new class of nitric oxide donor molecules
  • S-nitrosothiol biology and metabolism
  • Evaluation of the role of S-nitrosoglutathione reductase activity in asthma and other diseases
  • Assessment of nanotoxicology of inhaled drug delivery vehicles and the use of nanotechnology in diagnostics
Tel:
020 7848 4780
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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

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020 7848 3975
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Dr Royall's current research explores the relationship between solid state properties and the performance of pharmaceutical materials and medicines.
A major facet of this research involves characterising the amorphous form of drugs in isolation and within their dosage forms. An amorphous drug has a disordered structure, rapid dissolution and therefore has a higher bio-availability compared to its crystalline analogue.

The technical challenges required for analysing amorphous materials has lead to novel expertise in the area of screening poorly soluble drugs for potential development into amorphous medicines. Thermal analysis forms a strong theme throughout all of this work and so new applications and improvements on the state of the art are continuously being transferred into the research environment.
Dr Royall works within the Drug Delivery group which is a centre of expertise for the development of aerosol formulations and the analysis of the fate inhaled particles.

Forming respirable particles by either convergent (particle engineering) or divergent (milling) approaches often involves the formation and control of wholly or partially amorphous regions on the micron or nanometre scale. Thus his research directly impacts on the group’s output as it provides the means by which novel aerosol formulations maybe characterised and thus controlled.

Specific analytical expertise and capability:
  • Dynamic mechanical analysis: Powder pocket, humidity control & immersion.
  • Differential scanning calorimety
  • Solution calorimetry
  • Thermogravimetric analysis
  • Hot stage microscopy
  • Detection & quantification of amorphous / crystalline content
  • Screens for amorphous medicine development

Other interests:
  • Measuring the physical properties of chocolate
  • Measuring the physical stability of drugs and medicines
  • Characterising the dissolution of drug particles within lung fluids
Tel:
020 7848 4369
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Pharmaceutical salts
The group has developed assays to measure the interactions that occur in the liquid state when pharmaceutical salts dissolve in physiological fluids. The data generated from these assays are being used to develop dynamic drug ion-pairs that are able to control the delivery ionisable compounds into the tissues of the skin and lung

Ttriggered-nanoparticle-carriersriggered nanoparticle carriers
Pharmaceutically acceptable chemometric and thermometric mechanisms to trigger the drug release from soft nanoparticles carriers are being developed

Keratin-interactionsKeratin interactions
The keratin in skin, hair and nail tissues is being characterized in health and diseased tissues and new methods to control the delivery of active agents into and through keratin rich barriers is being developed.

Self assembling semi-solid matrices
Through the control of volatile solvent evaporation propellant driven sprays and foams can form self-assembling semi-solids that control drug delivery. The group is developing novel systems that present therapeutic molecules to biological barriers that possess the chemical and physical attributes to allow effective drug delivery.

Tel:
020 7848 4843
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The Pharmaceutical Biophysics Group, comprising Professor Jayne Lawrence, Dr David Barlow, Dr Andrew Chan, Dr Alex Drake, Dr Cécile Dreiss, Dr Richard Harvey, Dr James Mason, Dr Laila Kudsiova and Emeritus Professor Peter Quinn, aims to secure an understanding at the molecular level of the physicochemical and biological properties of small and macromolecules, lipid membrane systems and macromolecular drugs and drug delivery systems, through the combined application of advanced analytical techniques, including computer modelling, FT-IR, circular dichroism, Raman spectroscopy, static and dynamic light scattering, rheometry and dilute solution viscometry, atomic force microscopy, X-ray diffraction, small angle neutron scattering, neutron reflectivity and both liquid and solid-state NMR.

The group applies scientific principles and analytical techniques to identify, characterise and quantify biological molecules. This work is applied in both the kinetic and equilibrated states to the health related fields, drug disposition and metabolism, biochemical endocrinology, clinical chemistry and evidential analysis.


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Dr Chan research involves using infrared and Raman imaging spectroscopy to create images showing the distribution of different chemicals in a sample. He also employed these imaging methods to understand chemical interactions at the molecular level that are normally not available in ordinary microscopy. Dr Chan has been involved in the development of many new infrared spectroscopic imaging applications, particularly using the attenuated total reflection (ATR) imaging approach with different crystals including diamond, to study drug distribution in compacted pharmaceutical tablets, dissolution of pharmaceutical formulations in water, stability of pharmaceutical substances under controlled environments in a high-throughput manner, diffusion of chemicals in polymer film/fibre and biological tissues such as hair and skin. Dr Chan recent research interests also include label-free imaging of live cells, chemical process in microfluidic systems as well as tip enhanced Raman spectroscopy.
Tel:
+44 (0)207 848 4578
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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

Tel:
020 7848 3766
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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:
Neutron reflectivity, neutron diffraction, and small angle neutron scattering studies of drug and gene delivery systems and model membranes; bioinformatics and cheminformatics studies of traditional medicines; design, synthesis and characterisation of peptidyl biosurfactants; mitochondriotropic drug transprt systems for treatment of age-related neurological disorders.

Tel:
020 7848 4827
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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

Collaborations are with Dr Ken Bruce, Dr Alex Drake, Dr Sukhi Bansal, Dr Graham Mitchell, Dr Chris Lorenz, Dr Victoria Sanz-Moreno, Prof Tony Ng (all from KCL), Dr Dominic Campopiano (University of Edinburgh), Dr Antoine Kichler (Généthon, Evry, France), Dr Jenny Lam (Hong Kong University) and Dr Michael McArthur (Procarta Biosystems Ltd.).
Dr Mason's research is/has been supported by the MRC, BBSRC, The Wellcome Trust, the Hong Kong RFCID, Applied Photophysics Ltd and Procarta Biosystems Ltd.

Tel:
020 7848 4813
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Prof Lawrence's research has two main themes, namely the design, synthesis and characterisation (physico-chemical and biological) of surfactant systems (especially micelles, microemulsions and vesicles) intended for drug and gene delivery and the interaction of drug and gene delivery vehicles with biomembranes and the passage of biomolecules (especially drugs) across biomembranes.

A variety of techniques are used to achieve these goals including light, neutron and X-ray scattering, surface and interface characterisation and advanced spectroscopic techniques as well as cell culture models.
Tel:
020 7848 4808
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Dr Harvey's research is based around the use of physical techniques, from microscopy and optical spectroscopies to neutron scattering, in order to study phenomena associated with the aggregation behaviour and interactions of amphiphilic molecules in biological milieu.

Specific areas of interest include:
  • The role of aminoacyl lipids in the structure and function of bacterial membranes in relation to antimicrobial drug resistance.
  • The effect of antimicrobial peptides and polymers on aggregation behaviour and toxicity of lipopolysaccharides.
  • Physico-chemical studies of behaviour of charged and neutral lipids and surfactants in the binary and ternary mixtures commonly used in drug delivery vehicles.
Tel:
020 7848 4831
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The Pharmacology and Therapeutics Group comprises Dr Dom Spina, Professor Miles Houslay, Professor Clive Page, Dr Julie Keeble, Dr Ian McFadzean, Dr Simon Pitchford, Dr Manasi Nandi, Dr Sarah Salvage, and Emeritus Professor Peter Jenner. The Group has internationally-recognised expertise in Pharmacology and Therapeutics. The combined aim of the group is to further understanding of the mechanisms of human diseases and their treatment. Primary areas of pharmacological interest include the cardiovascular system, brain, lung, with expertise ranging from cell and molecular techniques to human studies.

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. Approaches involve the development and use of a number of models to further 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

Research by this group focuses on the biological systems underlying vascular physiology and pathophysiology in inflammatory and related disorders, including sepsis, arthritis and thermoregulatory dysfunction. Leading Principal Investigators are members of The Centre for Integrative Biomedicineand 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.

Neurodegenerative diseases

Work here focuses on the investigation of 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.


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Specific research areas:
  • 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
Tel:
020 7848 4784
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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.

Tel:
020 7848 4327
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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).
Dr Spina has been supported by various research councils (BBSRC, MRC) and industrial support since 1994.

Links with Industry

Dr Spina is currently collaborating with a number of industrial partners to further understand the role of different drug targets in the inflammatory response.

Tel:
020 7848 4341
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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.

Tel:
020 7848 6053
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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.

Tel:
020 7848 3401
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Nitric oxide is an important biological mediator that plays a variety of roles in cardiovascular, nervous and immune systems. Nitric oxide is synthesised from the substrate L-arginine by the enzyme nitric oxide synthase (NOS), of which three isoforms exist. Nitric oxide generation from the vascular endothelium is catalysed by the endothelial isoform of NOS (eNOS or NOS3). It behaves as a potent vasodilator and the regulated release of nitric oxide contributes towards the maintenance of normal endothelial function and hence blood pressure. Decreased endothelial nitric oxide signalling is associated with numerous cardiovascular diseases in humans. Similarly, deletion of the eNOS gene accelerates vascular disease pathogenesis indicating the importance of basal nitric oxide release on normal cardiovascular function.

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.
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020 7848 4446
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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.

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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

Tel:
020 7848 6018
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Dr Thomas' research projects focus on characterising the delivery of small molecule and biologic therapies across the blood-brain and blood-cerebrospinal fluid barriers in health and disease. An area of particular interest is membrane transporters and the relationship between drug concentrations in the CSF and the brain tissue. In order to understand molecule transport across these barriers she has developed and deployed a variety of experimental models. These range from in silico simulations through to cell culture and whole animal studies. She has also shared skills and expertise through several collaborations (e.g. Amgen, GSK, Ossianix, Institute of Psychiatry, University of Glasgow, London School of Hygiene and Tropical Medicine and Walter Reed Army Institute of Research, USA).
In 2012 Dr Thomas successfully led a multi-disciplinary team which secured an MRC DPFS grant to develop a safer more effective sleeping sickness drug using nanotechnology (NANOHAT). This latest award follows an earlier Wellcome Trust University Award for the investigation of the movement of sleeping sickness (human African Trypanosomiasis) drugs across the healthy and diseased blood-brain and blood-CSF barriers; and a Welcome Trust career development fellowship to study anti-HIV drug delivery into the CNS

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.

Tel:
020 7848 4102
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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.

Tel:
020 7848 4819
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Find out more about King’s researchers and research groups on the King’s Research Portal