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BSc, ARCS, PhD, FRSB
Department of Biological and Medical Sciences
Faculty of Health and Life Sciences
Rm SNC 3.06, Sinclair Building, Headington Campus
Senior Lecturer on the Medical Science and Biomedical Science (Module Leader BIOS6011 Clinical Biochemistry, BIOS4004)
Widening Participation Coordinator (Biological and Medical Sciences)
MSc Project Supervisor
2014-2021, Andy Blease, Collagen I dysfunction resulting in chronic osteoarthritis
2014-2018, Sara Falcone. Novel Models of Chronic Renal Disease (PhD).
2014-2018, Thomas Nicol. 2014. A novel model of mitochondrial dysfunction resulting in hypertrophic cardiomyopathy (PhD).
2017 – Pedro Romao (Diploma in Veterinary Medicine)
2012 – Hayley Tyrer. The role of HIF and hypoxia in acute and chronic mouse models of Otitis Media (PhD).
2011 - Sulzhan Bali. In vitro modelling of cellular processes in OM-BMDM studies in Junbo mice reveal defects in HIF and TGF-𝞫 signalling (PhD).
Collagen I dysfunction resulting in late-onset osteoarthritis
Abnormal branched chain amino acid metabolism is associated with sudden cardiac death
A novel model of Nephrotic Syndrome caused by a point mutation in Lama5
Extracellular matrix trunover in the glomerular basement membrane
Characterisation of a novel model of colitis
The association of a mutation in the C lectin binding domain of aggrecan with osteoarthritis and obesity
Background: Accumulation of extracellular matrix in organs and tissues is a feature of both ageing and disease. In the kidney, glomerulosclerosis and tubulointerstitial fibrosis accompany the decline in organ function, which is irretrievable with current therapies leading to inevitable kidney failure. Whilst histological and ultrastructural patterns of excess matrix form the basis of human disease classifications, the comprehensive molecular resolution of abnormal matrix is lacking.
Methods: Using mass spectrometry-based proteomics we resolved matrix composition over age in mouse models of kidney disease. We compared thechanges in mice with a global characterization of human kidney matrix during ageing and to existing kidney disease datasets to identify common molecular features.
Results: We found that ultrastructural changes in basement membranes are associated with altered cell adhesion and metabolic processes and with distinct matrix proteomes during ageing and kidney disease progression in mice. Within the altered matrix, we observed a reduction in basement membrane components (laminins, type IV collagen, type XVIII collagen) and a corresponding increase in interstitial matrix proteins (collagens I, III, VI, XV, fibrinogens and nephronectin) and this pattern was also seen in human kidney ageing. Indeed, this signature of matrix proteins was consistently modulated across all age and disease comparisons and the increase in interstitial matrix was also observed in human kidney disease datasets.
Conclusions: This study provides deep molecular resolution of matrix accumulation in kidney ageing and disease and identifies a common signature of proteins that provides insight into mechanisms of response to kidney injury and repair.
The number of people aged over 65 is expected to double in the next 30 years. For many, living longer will mean spending more years with the burdens of chronic diseases such as Alzheimer’s, cardiovascular disease, and diabetes. Although researchers have made rapid progress in developing geroprotective interventions that target mechanisms of ageing and delay or prevent the onset of multiple concurrent age-related diseases, a lack of standardized techniques to assess healthspan in preclinical murine studies has resulted in reduced reproducibility and slowed progress. To overcome this, major centres in Europe and the USA skilled in healthspan analysis came together to agree upon a toolbox of techniques which can be used to consistently assess the healthspan of mice. Here, we describe the agreed toolbox which contains protocols for echocardiography, novel object recognition, grip strength, rotarod, glucose and insulin tolerance tests, body composition, and energy expenditure. They can be performed longitudinally in the same mouse over a period of 4-6 weeks to test how candidate geroprotectors affect cardiac, cognitive, neuromuscular and metabolic health.
The link between mutations in collagen genes and the development of Alport Syndrome has been clearly established and a number of animal models, including knock-out mouse lines, have been developed that mirror disease observed in patients. However, it is clear from both patients and animal models that the progression of disease can vary greatly and can be modifed genetically. We have identifed a point mutation in Col4a4 in mice where disease is modifed by strain background, providing further evidence of the genetic modifcation of disease symptoms. Our results indicate that C57BL/6J is a protective background and postpones end stage renal failure from 7 weeks, as seen on a C3H background, to several months. We have identifed early diferences in disease progression, including expression of podocyte-specifc genes and podocyte morphology. In C57BL/6J mice podocyte efacement is delayed, prolonging normal renal function. The slower disease progression has allowed us to begin dissecting the pathogenesis of murine Alport Syndrome in detail. We fnd that there is evidence of diferential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an infammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function.
The proportion of the population over the age of 65 is growing the most rapidly due to the longevity revolution. Frailty is prevalent in this age group and strongly associated with disability and hospitalization, having a significant impact on the costs of health and social care. New effective interventions to delay or reverse frailty are urgently required. Geroprotectors are a new class of drugs, which target fundamental mechanisms of ageing and show promise in delaying the onset of or boosting resilience in frail older people. However, there are challenges to their clinical translation. Here we review the literature for evidence that frailty can be delayed or reversed and geroprotectors can improve frailty in murine models and in patients. We will then discuss the challenges, which make their clinical testing complex and propose potential options for moving forward.
One of the major challenges currently facing healthcare providers is an ageing population that is spending more time in ill-health. Many ageing individuals have multiple and complex needs which affect the ability to treat them effectively, which also has a significant impact on their own independence and quality of life. There are many aspects of testing interventions to improve health in old age in pre-clinical models; from breeding strategies to measurements of outcomes. Here we provide a brief overview of the major considerations to take into account in such studies and the limitations or challenges we face in these studies.
Isocitrate dehydrogenase (IDH) is an enzyme required for the production of α-ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria for ATP production, and is a tetramer made up of two α, one β and one γ subunit. Loss-of-function and missense mutations in both IDH3A and IDH3B have previously been implicated in families exhibiting retinal degeneration. Using mouse models, we investigated the role of IDH3 in retinal disease and mitochondrial function. We identified mice with late-onset retinal degeneration in a screen of ageing mice carrying an ENU-induced mutation, E229K, in Idh3a. Mice homozygous for this mutation exhibit signs of retinal stress, indicated by GFAP staining, as early as 3 months, but no other tissues appear to be affected. We produced a knockout of Idh3a and found that homozygous mice do not survivepast early embryogenesis. Idh3a−/E229K compound heterozygous mutants exhibit a more severe retinal degeneration compared with Idh3aE229K/E229K homozygous mutants. Analysis of mitochondrialfunction in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both Idh3aE229K/E229K and Idh3a−/E229K cells. Loss-of-function Idh3b mutants do not exhibit the same retinal degeneration phenotype, with no signs of retinal stress or reduction in mitochondrial respiration.It has previously been reported that the retina operates with a limited mitochondrial reserve capacity and we suggest that this, in combination with the reduced reserve capacity in mutants, explains the degenerative phenotype observed in Idh3a mutant mice.
A great majority of genes present in the human genome are also present in the mouse, thus making it an attractive mammalian model organism to study gene function and dysfunction. Over the past few decades, the ability to manipulate the mouse genome has been developed in a variety of ways. A complementary methodology to create mutations in the mouse is to use chemical mutagenesis. N‐ethyl‐N‐Nitrosourea (ENU) is the mutagen of choice for creating random point mutations model organisms. Advances in sequencing technologies have resulted in a rapid identification of the causative mutation. ENU mutagenesis is a powerful hypothesis‐generating approach to create new mouse models through both forward and reverse genetics approaches. Furthermore, the addition of challenges can identify mutations affecting specific pathways, and specific mutant lines or strains can be used to identify modifiers.
Kyphosis and scoliosis are common spinal disorders that occur as part of complex syndromes or as nonsyndromic, idiopathic diseases. Familial and twin studies implicate genetic involvement, although the causative genes for idiopathic kyphoscoliosis remain to be identified. To facilitate these studies, we investigated progeny of mice treated with the chemical mutagen N‐ethyl‐N‐nitrosourea (ENU) and assessed them for morphological and radiographic abnormalities. This identified a mouse with kyphoscoliosis due to fused lumbar vertebrae, which was inherited as an autosomal dominant trait; the phenotype was designated as hereditary vertebral fusion (HVF) and the locus as Hvf. Micro–computed tomography (μCT) analysis confirmed the occurrence of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae in HVF mice, consistent with a pattern of blocked vertebrae due to failure of segmentation. μCT scans also showed the lumbar vertebral column of HVF mice to have generalized disc narrowing, displacement with compression of the neural spine, and distorted transverse processes. Histology of lumbar vertebrae revealed HVF mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centers. Genetic mapping using a panel of single nucleotide polymorphic (SNP) loci arranged in chromosome sets and DNA samples from 23 HVF (eight males and 15 females) mice, localized Hvf to chromosome 4A3 and within a 5‐megabase (Mb) region containing nine protein coding genes, two processed transcripts, three microRNAs, five small nuclear RNAs, three large intergenic noncoding RNAs, and 24 pseudogenes. However, genome sequence analysis in this interval did not identify any abnormalities in the coding exons, or exon‐intron boundaries of any of these genes. Thus, our studies have established a mouse model for a monogenic form of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae, and further identification of the underlying genetic defect will help elucidate the molecular mechanisms involved in kyphoscoliosis.
An increased lifespan comes with an associated increase in disease incidence, and is the major risk factor for age-related diseases. To face this societal challenge search for new treatments has intensified requiring good preclinical models, whose complexity and accuracy is increasing. However, the influence of ageing is often overlooked. Furthermore, phenotypic assessment of ageing models is in need of standardisation to enable the accurate evaluation of pre-clinical intervention studies in line with clinical translation.
The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep.
This article gives an overview about the aging in rodents and how rodents can be used for aging modelling. The article starts with more general consideration about the modelling and some basic background. It is followed by the review of the most common progeroid syndromes along with the molecular mechanisms of aging. Then the effect of caloric restriction is described in deeper details. And finally, the role of transposable elements and the role of their activation during aging is described. Therefore, present article covers broadly the modelling of aging in the rodents with some more detailed overviews for the mechanisms explaining the potential interventions to modify the aging and aging related problems.
Fellow of the Royal Society of Biology
Honorary Senior Lecturer, Section of Renal and Vascular Inflammation, Imperial College London
Member of the Centre for Osteoarthritis Pathogenesis funded by Versus Arthritis, Kennedy Centre, Oxford
Member of the Society for Experimental Biology and Medicine
Editorial Board; Experimental Biology and Medicine
Jerome S. Brody Annual Lecture, Boston University School of Medicine, Jan 2018
Invited Speaker,Swiss Lab Animal Science Association, November 2017
British Society for Cardiovascular Research Autumn Meeting: Cardiac Metabolic Disorders and Mitochondrial Dysfunction, oral presentation, poster presentation, September 2017
Invited Speaker, 2nd European Advanced School for Mouse Phenogenomics, June 2017
Invited Speaker, Oxford NC3Rs day, Ageing and Phenotyping, February 2017
Invited Speaker, 7th Molecular Pharmacology Workshop on Osteoarthritis, 2016
Invited speaker, INFRAFRONTIER Industry and Innovation workshop, June 2016
Invited Keynote presentation, International Ageing and Matrix Conference, Wellcome Trust Centre for Cell Matrix Research, September 2015
Invited Speaker, European Teratology Society meeting, September 2015
International Alport Syndrome Workshop, 2015, best oral presentation prize
Cutting Edge Osteoarthritis, 2015, Poster (1st prize)
British Society for Research into Ageing, Annual meeting, 2014, 2 selected oral presentations
International Alport Syndrome Workshop, 2014, oral presentation
Head of Disease Model Discovery, Mammalian Genetics Unit, Medical Research Council, Harwell (Sept 2010 to April 2018), Honorary Senior Lecturer (September 2009-Oct 2011, Kennedy Institute for Rheumatology, Imperial College)
London Technology Network Business Fellow (March 2010-Oct 2011)
Head of Mutagenesis (Nov 2007 – Aug 2010), Deputy Scientific Manager (Nov 2006 – Oct 2007), Mary Lyon Centre, Medical Research Council, Harwell
Research Associate (reporting to Prof M. Botto, Prof Mark Walport)Faculty of Medicine, Imperial College (Hammersmith Hospital), London: Rheumatology Section(Nov 1999 – October 2006)
Research Associate (reporting to Dr. K. Gould) ICSM (St. Mary’s Hospital), London: Department of Immunology (Jan 1998 – Oct 1999)
Research Associate (reporting to Dr. A. Kelly) Guy’s Hospital, London: Renal Laboratory, Department of Medicine (July 1994- Jan 1998)
Research Assistant (reporting to Dr. A.K. So) RPMS, Hammersmith Hospital, London: Rheumatology Unit (Jan 1988- July 1994)
Research Assistant (reporting to Dr. John Harfield) Coulter Electronics, Luton (1983-1988) Particle sizing lab