Professor Sir Munir Pirmohamed is currently David Weatherall Chair in Medicine at the University of Liverpool, and a Consultant Physician at the Royal Liverpool University Hospital. He is Director of the MRC Centre for Drug Safety Sciences, and Director of the Wolfson Centre for Personalised Medicine. He is also an inaugural NIHR Senior Investigator, and Fellow of the Academy of Medical Sciences in the UK. He has authored over 450 peer-reviewed publications, and has an H-index of 92 (Google Scholar). His research focuses on genomic and non-genomic technologies that can be developed and used to progress the field of personalized medicine in an evidence-based, cost-effective and equitable manner. Given his background in clinical pharmacology, most of his research focuses on the use of medicines with the aim of improving their efficacy and minimizing their toxicity, thereby optimizing their harm-benefit ratio.
The main theme of Kevin’s research has been to investigate the role of drug disposition in drug response, both pharmacological and toxicological, which led to him founding the MRC Centre for Drug Safety Science in 2009. His research interests span clinical pharmacology, basic pharmacology/toxicology and medicinal chemistry. A major focus of his present work is to investigate clinical, cellular, molecular and chemical mechanisms of adverse drug reactions in man in an integrated fashion, with the long-term goal to develop a rational approach to their prediction and prevention. Adverse drug reactions are a major complication of drug therapy which cause a great deal of patient morbidity and may also result in mortality. Drug toxicity is now considered a major cause of chemical toxicity in man. We have chosen to focus primarily on the fundamental mechanisms involved in those adverse drug reactions which occur in man but are not predictable from present preclinical evaluation.
Ana’s primary focus is on pharmacogenetics and personalised health. She has been working on identification of genetic predisposing factors for adverse drug reactions including immune-mediated hypersensitivity, hepatotoxicity, agranulocytosis and statin-induced myotoxicity using high throughput genotyping and next generation whole genome (genomic DNA and mitochondrial DNA) and whole exome sequencing technologies. Ana has also worked on adverse reactions to drugs used in pregnancy and childbirth, where she integrated big data using multi-omic approaches and clinical data to identify biomarkers that may be utilized in clinical practice. Further research interests include implementation of genetic testing in the NHS, development of clinical decision support systems and tackling health inequalities. Ana is Professor of Pharmacology and Personalised Medicine.
Dan’s research focuses on understanding the mechanisms of pathogenesis, and identifying prognostic biomarkers of the severe cutaneous adverse drug reactions (ADRS) Stevens-Johnson syndrome and toxic epidermal necrolysis. He has a particular interest in the development of novel in vitro models utilising induced pluripotent stem cells derived from ADR patient PBMCs for advancing our understanding of what predisposes certain individuals to drug-induced skin blistering reactions. Furthermore he has a long held interest and expertise in the study of pharmacogenomics of adverse drug reactions spanning a wide range of therapeutics and clinical disciplines.
Drug-induced mitochondrial toxicity is a major pathway in adverse drug-reactions across many organs. However, there is little evidence of how this pathway translates to the clinical onset of toxicity in certain individuals. Therefore the research of the Bioenergetic Group, led by Amy, is focused upon elucidating the fundamental mechanisms of drug-induced mitochondrial dysfunction and translating this knowledge to define the molecular and genetic factors underlying individual susceptibility to mitotoxicants. The group currently focusses on liver and muscle toxicity and work with a range of in vitro models including transmitochondrial cybrids, primary hepatocytes, HepaRG cells and myobundles.
Having worked on understanding fundamental mechanisms of apoptosis for many years, some of Gerry's current work concentrates on utilising this knowledge in improving current cancer treatments using chemotherapy. In research funded by NWCR, his group is currently establishing a method known as BH3 profiling. This method can then be used to ascertain whether different individuals will be sensitive or resistant to different chemotherapeutic agents. Other aspects of his current research involve understanding both apoptotic and non-apoptotic roles of BCL-2 family proteins and the further understanding the significance of a novel endoplasmic reticulum stress response recently identified in his laboratory.
Ian’s research focuses on understanding the mechanisms by which cells sense and adapt to chemical entities (particularly therapeutic drugs) and how this influences the balance between efficacy and toxicity. A current focus is the NRF2 stress response pathway, which controls the expression of a range of cytoprotective genes in mammalian cells. Ian’s research focuses on better understanding the types of stress that NRF2 protects against, how it does this, and whether measuring this response can help us to predict the toxic side effects associated with existing and new medicines. He is also interested in the potential of NRF2 as a new therapeutic target in several diseases.
Mike’s research focuses on cardiac disease with a specialist interest in adverse effects of cancer drugs on cardiac physiology. The long term aim is to gain a greater understanding of the cellular mechanisms of cardiac disease and drug induced cardiovascular toxicity. Mike’s team utilise advanced multi-cellular cardiac microtissues to emulate cardiac physiology allowing them to study functional and structural changes in multiple cardiac cell types. Recent research has also focussed on the pleiotropic vascular protective effect of statins and how these drugs can directly affect cardiac physiology.
Dr Lekh Dahal
Lekh developed an interest in a new class of adjuvants that target the Stimulator of Interferon Genes (STING) pathway, which have opened up avenues to reprogram the tumour microenvironment and curb loco-regional immunosuppression. He is also interested in understanding the molecular basis of immune regulation by naturally occurring alternatively-spliced soluble isoforms of crucial immunomodulatory receptors (such as CTLA-4, 4-1BB, PD-1). He hopes to better understand how modulation of these immune receptors in cutting-edge cancer therapy can also drive adverse drug reactions.
The focus of David’s research group is on blood-brain barrier transporters. This research lies at the interface of drug transporters, blood-brain barrier (BBB) biology and molecular properties that determine the mechanism of transporter action. During his career, David has developed skills in biochemistry, molecular cell biology, drug transporter pharmacology and in vitro models of the BBB. The BBB is considered a significant bottleneck to the development of new CNS treatments with the additional challenge of disease specific effects. David’s recent novel findings include identifying lamotrigine as a substrate for OCT1, determining that ABT-263 is a P-glycoprotein substrate, characterising gabapentin as a LAT1 substrate and defining LAT1s interaction with cholesterol.
Carrie’s research interests are focused on the regulation of gastrointestinal architecture and the maintenance of gut homeostasis with a focus on the intestinal epithelium. Her lab aims to target the processes and mechanisms responsible for this breakdown of intestinal barrier function, epithelial cell destruction and inflammation in order to develop novel therapeutic approaches. They have recently identified the NF-κB2 transcription factor as an important regulator of intestinal epithelial damage in murine in vivo models and in intestinal organoid culture, and are currently developing novel methods to modulate the NF-κB2 signalling pathway to prevent injury to the intestinal epithelium.
Chris has more than twenty years of experience of molecular bioanalysis, working with cell culture and in vivo models, mainly to improve our understanding of drug-induced liver injury (DILI). He led the molecular and cellular toxicology group within the Centre for the recent Mechanism-based Improved Prediction of Drug-Induced Liver Injury (MIP-DILI) IMI programme. He plays a leading role in the new IMI project TransQST, which will develop quantitative systems toxicology models to improve our understanding of adverse drug reactions, as well as the new IMI Transbioline biomarker consortium. He recently led the liver project in the UK Regenerative Medicine Safety platform, developing innovative methods for the assessment of the safety of stem cells and regenerative therapies, including cell labelling using nanoparticles and cell tracking. Chris works closely with clinical colleagues at Aintree to develop better in vitro models of the liver, and through this collaboration he also has interests in liver regeneration and cholangiocarcinoma. Chris has been Programme Director for the Pharmacology BSc degree at the University of Liverpool since 2012.
Xiaoli’s research focuses on understanding the mechanisms of drug hypersensitivity by defining the chemistry of the molecules that drive the reactions. She has established bioanalytical platforms to quantitatively and qualitatively characterise drug-metabolites and drug-protein adducts in vitro and in patients using mass spectrometry and proteomics. Led by Xiaoli, the immunopeptidomics group currently focuses on the identification of naturally processed and presented antigenic peptides that could initiate an immune response. Comprehensive knowledge of antigenic peptides and their relationship with human leukocyte antigen is crucial for designing innovative cancer immunotherapy and better diagnostic assays for drug hypersensitivity among other autoimmune diseases.
Andrew is Professor of Statistical Genetics in the Department of Biostatistics. His research focusses on the development, evaluation and application of methodology for the analysis of genome-wide association and sequencing studies. Key themes of his research include the aggregation of genetic data from diverse populations through trans-ethnic meta-analysis and fine-mapping of complex trait loci through integration with epigenomic and transcriptomic resources to identify causal genes underlying common human disease. He has co-led international collaborative efforts to enhance understanding of a wide range of complex traits, including type 2 diabetes, obesity and kidney function. His team have also focussed on the development of software tools to enable efficient analysis of “time-to-event” outcomes in pharmacogenetic studies of adverse drug reactions and treatment efficacy.
Sudeep Pushpakom’s major research focus is in addressing drug safety using in vitro, pharmacogenetic and clinical models, particularly in the area of cardiometabolic disease and renal toxicity. His research use omics approaches to understand the pathogenic mechanisms that lead to drug-induced toxicity; for the identification of translational biomarkers to predict toxicity and stratify patients; and, to investigate therapeutic reversal strategies. Translational work carried out by Sudeep in the area of HIV drug safety has already led to a NIHR-EME funded phase 2 interventional trial (TAILoR trial) which investigated the efficacy of drugs in reducing insulin resistance in HIV-positive patients. He has also published on pharmacogenetics of infectious diseases and drug-associated renal injury and is actively involved in drug repurposing studies.
Cells in virtually all tissues are in contact with organized complexes of structural molecules collectively called the extracellular matrix (ECM). ECM induces a variety of signals that regulate the behavior of cells. As a consequence, tissues or organs keep their normal architecture and homeostasis. Aberrations in signal transduction from the ECM cause chronic degenerative and fibrotic disorders, and cancer progression. The focus of our research group is how drugs affect extracellular matrix (ECM) architecture and how dysregulation of cell-ECM interactions by drugs causes chronic fibrotic disorders and cancer. We utilize extensive mouse genetic approaches, including conditional knockout technology.
Parveen's research focuses on cardiac and liver disease with a specialised interest into drug induced toxicity. The long term aim is to gain a greater understanding of the cellular mechanisms that result in disease, emphasising on key mechanisms and pathways of disease in order to identify clinically relevant therapeutic targets and early detection biomarkers. Parveen's team have a specialised focus on membrane protein physiology, cellular toxicity and the development of 3D cell culture models that emulate more in vivo like structures. For these experiments they apply conventional cell biology and biochemical techniques together with immunofluorescence as well as advanced proteomics and bioinformatics.
Shankar's laboratory is interested in exploring the potential use of small mall inhibitors of the BCL-2 family, also known as BH3 mimetics, in cancer therapy. They study this by assessing – (a) the effectiveness of BH3 mimetics as single agents or in combination with existing therapy in haematological malignancies and cancers of the head and neck as well as pancreas, (b) the role of metabolism in BH3 mimetic-mediated apoptosis, and how that can be exploited in a therapeutic context, and (c) the cellular and molecular mechanisms of BH3 mimetic-mediated apoptosis.
Immune checkpoint inhibitors are medicines that are used in the treatment of cancer to help the body’s own immune system attack the cancer cells. They have been shown to be highly effective but are associated with autoimmune reactions, such as skin rash, which can cause distress to the patient and prevent further courses of treatment being administered. Vincent’s research is focused on understanding the mechanisms of cutaneous toxicity, using modern laboratory techniques such as CyTOF and tissue samples from patients, so that we can avoid these reactions in future drugs and develop treatments for the autoimmune reactions.