Research

Here at the Department of Human Metabolism, our research strengths are in the fields of musculoskeletal disorders, reproductive medicine, endocrinology and diabetes.

We have a strong tradition of applying our high quality research to clinical practice for the benefit of our patients. For more information on any of the topics mentioned below, please follow the links to the staff pages of our senior researchers.

Musculoskeletal disorders

We carry out research across the spectrum of musculoskeletal disorders, from the basic cellular biology of bone through to clinical research into musculoskeletal disorders such as osteoporosis, osteogenesis imperfecta and arthritis. Our research goals are ultimately to improve the outcomes of both adult and paediatric patients with these diseases. We can loosely categorise our research into four main areas: (i) understanding the basic biology of bone and disease processes, (ii) studying the effects of a condition or treatment, (iii) characterising disease processes and (iv) examining determinants or predictors of disease in patients.

(i) Basic biology of bone disease and disease processes

Studies into the biology of bone, and the way in which the cells within it are able to orchestrate bone formation, maintenance and resorption are fundamental to the understanding of disease mechanisms.  Professor Ilaria Bellantuono studies the biology of bone marrow stem cells with particular emphasis on mesenchymal stem cells. Her focus is the mechanisms of mesenchymal stem cell migration, differentiation into osteoblasts, and discovery of novel therapies to combat ageing-related changes. Dr Alison Gartland's research interest is based on understanding the basic cellular and molecular mechanisms responsible for musculoskeletal disease and cancer, with an emphasis on the role of extracellular ATP and P2 receptors. Professor Tim Skerry's long-term interest is the mechanisms underlying the response of bone to loading; his research is aimed at identifying novel mechanically regulated signalling pathways in bone.

Developments from Tim’s previous research have led to studies into the regulation of cell surface hormone receptors by accessory proteins and, through the spin-out company Medella Therapeutics, preclinical development of antibody and small molecule drugs.

Image of metal on metal hip replacementProfessor Mark Wilkinson leads research in the field of joint disease and replacement, studying the responses of the patient to joint prostheses and how these effects can be modified. Specifically, at a fundamental level, Mark with Alison Gartland study the effect of metal ions released by prostheses on bone cell activity.

Our researchers have active collaborations with other departments in the University. The INSIGNEO group in the Department of Mechanical Engineering has a strong focus on musculoskeletal modelling from the basic biology of cell signalling networks (Tim Skerry) through to the development of virtual physiological models of the musculoskeletal systems of animals and man (Ilaria Bellantuono). Dr Steve Renshaw from the MRC Centre for Development and Biomedical Genetics has expertise in the use of zebrafish and in inflammation, which links with studies on models of skeletal ageing by Ilaria Bellantuono, who also collaborates with the Centre for Stem Cell Biology (Professor Harry Moore) in the use of embryonic stem cells in bone regeneration. A collaboration with Professor Joe Harrity in the Department of Chemistry is focused on the design of novel small molecule drugs for cancer and bone disease (Tim Skerry).

(ii) Studying the effects of a condition or treatment

Professor Richard Eastell is the Director of the Mellanby Centre for Bone Research.  He leads research on the effects of a range of drugs (for example, bisphosphonates such as zoledronic acid; teriparatide; 11-beta HSD inhibitors) and conditions (obesity, chronic kidney disease) on various aspects of the skeleton, including bone turnover and fracture healing. Professor Nick Bishop, the UK's only Professor of Paediatric Bone Disease, leads a group whose focus is treating children’s bone diseases such as osteogenesis imperfecta and hypophosphatasia. Part of this work entails the development of new biomarkers, such as microindentation and bone turnover in response to short term whole body vibration, that can be used as proxy outcomes for phase 2 studies, as well as examining early influences of vitamin D and mechanical loading on skeletal growth. Professors Eugene McCloskey and Tim Skerry are investigating the strain induced by commercially available vibrating footplates on bone, specifically the tibia. These vibrating platforms could help strengthen bone in people who are not physically able to engage in more strenuous exercise. Tim is further examining the interactions between loading/exercise and other stimuli, such as diet, in regulating anabolic skeletal responses.

(iii) Characterising disease processes

For effective treatment, it is necessary to understand disease processes and how they interact with other body systems. We have a strong tradition of collaboration with other departments and institutions to bring a multidisciplinary approach to clinical problems. We are currently working with staff at the Sheffield Teaching Hospitals NHS Trust and using the latest in bone biochemistry and imaging techniques to characterise metabolic bone disorders brought on by chronic kidney disease, which results in increased risk of fracture.

We are researching the cellular and molecular mechanisms of tumour-induced bone disease. Dr Colby Eaton, whose focus is on prostate biology and cancers, is examining the mechanisms by which tumour cells maintain or escape quiescence to establish and metastasise. We are studying the role of the lysyl oxidase family of proteins and their regulation in cancer (Alison Gartland, Tim Skerry). Tim is also carrying out research into the modification of cell signalling, specifically involving signalling via cell surface receptors that associate with receptor activity modifying proteins (RAMPS). Our emphasis is on pharmacological approaches to receptor modulation as a therapeutic option in bone disease and cancer.

Collaborations within the university include studying long-term survivors of cancer with staff from the Academic Units of Diabetes, Endocrinology & Metabolism (Richard Ross) and Reproductive and Developmental Medicine (Allan Pacey); effects on cardiovascular health with the Department of Cardiovascular Science (Chris Newman); and the effects of treatment of breast cancer on bone health with the Department of Oncology (Robert Coleman).

(iv) Examining determinants or predictors of disease

The ability to predict disease processes or outcomes of treatment based on a patient’s characteristics (age, Bone2body mass index, gender, genetics) is valuable in the clinic, and expected to become more so with an increasing emphasis on personalized medicine. One such example is FRAX®, an online tool for calculating 10-year fracture risk. We have a number of projects aimed at identifying at-risk patients to allow for earlier intervention. One of the major contributors to poor bone health is a low level of vitamin D, which is widespread in the UK. Identifying patients who are likely to have low levels based on their characteristics allows for appropriate treatment and advice to prevent the development of more difficult-to-treat bone disorders.

Dr Lang Yang's finite element modelling of the hip is increasing our knowledge and understanding of the microarchitecture of the hip, helping physicians to identify patients at risk of hip fracture. In a related project, we are examining endocrine determinants of vertebral fracture. We also study the genetic determinants of musculoskeletal conditions, including joint shape, arthritis and genotype as a predictor of responses to prostheses and surgical outcomes (Mark Wilkinson).

CT-based finite element modelling of boneIn Child Health, Nick Bishop and his team are using whole bone quantitative computed tomography to study the relationship between bone architecture and genotype, examining the relationship between fat and bone in the growing skeleton, deep phenotyping in bone fragility disorders, and determining whether heterozygous mutations in genes known to cause severe osteogenesis imperfecta can increase fracture risk.

Dr Amaka Offiah's work concentrates on paediatric imaging, to optimise methods of distinguishing brittle from normal bones. Her research is key in identifying children who are the victims of abuse by the detection and dating of the subtle fractures seen in abuse as opposed to those in children with skeletal dysplasia. She is also involved in improving existing modalities and developing new techniques for imaging children's bones and muscles that reduce or completely avoid exposure to the harmful effects of X-rays. Dr Offiah was also the 2013 Royal College of Radiology Roentgen Professor, and has travelled the country inspiring young radiologists to become researchers of the future.

Sheffield Musculoskeletal Biobank

The Academic Unit of Bone Metabolism within the University of Sheffield manages the Sheffield Musculoskeletal Biobank. Our research interests span skeletal diseases of childhood through to the elderly person, and cover both benign and malignant bone disease. Our clinical research covers areas of metabolic bone diseases including osteoporosis, childhood bone diseases, tumour-induced bone diseases, such as multiple myeloma and metastatic bone disease, and osteoarthritis and prosthesis-related bone loss.

The aim of the biobank is to make use of these clinical and tissue resources to address research questions relevant to musculoskeletal disease. The biobank holds tissue samples obtained from donors, or completed, ethically approved projects with appropriate consent for biobank storage and use for future research projects. The biobank operates under the guidance of a steering committee to assure compliance with current best ethical practice.

A list all the projects that have been approved by the SMB and a lay summary for the most recent can be found here.

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Reproductive and developmental medicine

Professor Allan Pacey leads research within this unit, which covers the spectrum of female reproduction from the molecular mechanisms regulating follicle development to macroscopic analysis of the cervix using electrical impedance spectroscopy. 

Professor Allan Pacey is Head of Andrology for Sheffield Teaching Hospitals and his research focus is the biology of human spermatozoa and aspects of semen quality and fertility in men. This includes applying modelling techniques to study the mechanics of sperm motility and the role of microorganisms in premature sperm death. His work influenced the acclaimed "Great Sperm Race", which was screened in five countries and inspired public debate on conception and fertility.

Professor Alireza Fazeli's work focuses on the cross-talk between gametes and embryos, and the maternal tract. He is characterizing the innate immune system within the female reproductive tract along with the role of Toll-like receptors in female fertility. Please see his laboratory pages for more information.

Dr Mark Fenwick focuses on the regulation of follicle development in the mammalian ovary. In particular, he is interested in the early, gonadotrophin-independent stages and how various signalling pathways are used to establish gradients and communication networks in a three-dimensional context. His aim is to understand how the ovary, with its limited supply of oocytes, is able to selectively encourage some follicles to develop in a timely manner, while others remain in a relatively quiescent state. Mr Hany Lashen's work investigates the impact of genetics, development and the environment on ovarian development. This includes the ovarian response to GnRH agonists and antagonists; the impact of anthropometry on ovarian response to controlled simulation; and the endocrinological, metabolic, social and developmental aspects of polycystic ovary syndrome and hirsutism. He is also looking at hyperandrogenism as a function of the interaction between development and the genome and its impact on cardiovascular risk in teenage girls.

Dr Neil Chapman's interests lie in gene regulation by the nuclear factor kappaB family of transcription factors, and their effect on myometrial function during pregnancy and labour. His work focuses on prevention of premature birth.  This work was the focus of an article by the BBC - http://www.bbc.co.uk/news/health-21628912http://www.bbc.co.uk/news/health-21628912

MRI of developing fetusProfessor Dilly Anumba’s research into maternal and fetal physiology and medicine has both laboratory and clinic-based themes. He investigates the physiology and pathology of human pregnancy and birth, and the innate immune and inflammatory mechanisms that underpin disorders of parturition, including conditions like recurrent pregnancy loss, hypertension in pregnancy and fetal growth restriction. He is developing innovative markers and devices for the prediction of premature birth, aiming to translate discoveries into novel spectroscopic and imaging techniques to help determine tissue remodelling changes that may predict preterm labour. He is using new biomechanical and modelling approaches to fetal imaging to enhance fetal diagnosis and therapy.

 Over the last decade, Dr Elspeth Whitby has been assessing the value of magnetic resonance (MR) imaging of the fetus in clinical practice and developing additional sequences to image specific pathologies. She has established links with psychology to study how the brain structure, as seen on imaging, relates to development in the term and premature infant. Collaboration with social sciences allows her to look at the sociology of health, science and technology in fetal imaging and its impact in society. She has recently started studying the placenta using MR, focusing on developing sequences that can determine whether the placenta has invaded the uterine wall, by how much and where. In all areas of research, Dr Whitby's aim is to translate her results into clinical practice as soon as possible.

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Endocrinology

Endocrinology is the study of hormones and their effects on the body. Our laboratory and clinical groups are working under the guidance of Professor Richard Ross and Professor John Newell-Price to define the best methods for assessing and treating disorders of hormone excess and deficiency. They are specifically focusing on pituitary, adrenal and gonadal disorders. The pituitary, a gland at the base of the brain, plays a central role in regulating body composition, metabolism and fertility. Pituitary hormone deficiency is common in patients with pituitary disease, usually caused by benign tumours. By contrast, some pituitary tumours produce excess hormones, such as in acromegaly and Cushing’s Disease. Appropriate treatment of pituitary hormone imbalance has a profound effect on morbidity, mortality and quality of life for patients with pituitary disease. The adrenal gland produces the stress hormone cortisol and an excess occurs in Cushing’s syndrome and a deficiency in Addison’s disease and congenital adrenal hyperplasia. In gonadal disorders, the team is working on testosterone replacement in young adult male cancer survivors with hypogonadism.

Diurnal logoIn the laboratory, we are examining the mechanism by which hormones signal through their receptors, and developing new long-acting biological drugs to stimulate and block hormone receptors. We have two spun out two companies from the unit: Asterion Ltd. is developing long-acting growth hormone agonists and antagonists, and Diurnal Ltd. is developing new treatments for adrenal insufficiency and congenital adrenal hyperplasia.

Dr Phil Watson, with Professor Anthony Weetman and Dr Helen Kemp from the Medical School, is investigating the pathogenesis of autoimmune endocrine disease, with particular emphasis on thyroid autoimmunity. We are pursuing a number of research objectives: the cloning and characterisation of novel autoantigens, the isolation and functional expression of patient autoantibodies, investigation of the autoreactive T cell receptor gene repertoire, and a genome-wide screen (in association with the Wellcome Centre for Human Genetics) for disease susceptibility and risk loci.

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Diabetes

(i) Hypoglycemia and diabetes

We have a long-standing interest in the pathophysiology and clinical consequences of hypoglycaemia in patients with diabetes. Our current programme, led by Professor Simon Heller, has previously been funded by the Juvenile Diabetes Foundation International and Diabetes UK to investigate the causes of Dead in Bed syndrome. This describes the sudden death of young people with diabetes, who are around three times more likely to suffer this than the normal population. Our current hypothesis centres upon abnormal cardiac repolarisation induced by hypoglycaemia as the basis of this increased risk in patients with diabetes.

Studies in our laboratory have demonstrated that these abnormalities are caused in part by falls in potassium and rises in adrenaline, and we have shown that graded infusion of adrenaline can induce increases in QT interval even when potassium is maintained at normal levels using an exogenous infusion. Together with Paul Sheridan (cardiologist), we are measuring cardiac action potentials during experimental hypoglycemia in invasive electrophysiological studies.

We have also investigated the effects of hypoglycaemia on cardiac repolarisation in individuals with type I diabetes and cardiac autonomic neuropathy, and we are extending this to investigate the interaction with hypoglycaemia unawareness.

Our more recent focus is on the cardiovascular effects of hypoglycaemia in patients with type 2 diabetes. Hypoglycaemia has been associated with increased cardiovascular mortality in trials of intensive glycaemic control and we have identified a number of plausible mechanisms that may contribute to this observation. Funded by the National Institute of Health Research (NIHR), we are investigating electrophysiological and atherothrombotic changes during induced hypoglycaemia in patients with type 2 diabetes using both an experimental model of hypoglycaemia in the Clinical Research Facility and studies involving ambulatory electrocardiography monitoring and continuous glucose monitoring.

(ii) Educating patients in self-management of blood glucose levels

Our other main area of interest is the development and evaluation of complex interventions to promote self-management in adults and adolescents with type 1 diabetes. Sheffield was one of three original centres in the Dose Adjustment For Normal Eating (DAFNE) trial, which has now been rolled out to over 70 secondary care centres within the UK. We have recently completed a 5-year funded NIHR programme grant using DAFNE as a research test-bed. As a direct result of some pilot work within this programme grant, Health Technology Assessment have sponsored a multi-centre randomized controlled trial to examine the effectiveness of insulin pump therapy: Relative Effectiveness of Pump Therapy Over Structured education (REPOSE). We've also conducted pilot work aimed at hypoglycaemia restoration awareness (DAFNE-HART), which we plan to progress further by performing a larger feasibility trial. The adolescent intervention has been in collaboration with colleagues from the psychology department. An age-banded education course has been developed, Working with Carbohydrates, Ketones and Exercise in Diabetes (WICKED), with which we plan to perform a larger feasibility trial. We are also developing complex interventions to promote physical activity and self-management in type 2 diabetes.

(iii) Central nervous system imaging and diabetes

We are a multi-disciplinary diabetes and neuroimaging research collaboration, focusing on the use of state-of-the-art MR imaging for neuroscience research. We use this imaging to improve basic understanding of how diabetes affects the central nervous system (brain and spinal cord) and to translate these findings into clinical applications.

Our basic and translational research includes:

  • Investigations into the functional processes in the brain involved in the subjective experience of pain in diabetic neuropathy, including the observation of robust activation patterns in response to nociceptive stimuli.
  • Novel MR perfusion studies to identify objective, perfusion correlates of pain in diabetes with the potential for the development of new and more effective analgesic compounds that specifically target key perfusion correlates of painful diabetic neuropathy
  • Studies using non-invasive MR neuroimaging to understand neurodegenerative brain changes that occur in diabetes. We are currently examining the organisation of anatomical brain connections and how they relate to regional brain function in diabetic neuropathy.
  • Stroke and diabetes: studies into cerebrovasculature alterations in diabetes to identify the pathological changes that occur to explain the increased risk of stroke in this population. We aim to develop new approaches to facilitate quantification of risk and prediction of functional recovery post stroke.