Integrative Systems Supervisors

Theme Leader: Professor Stephen Bloom

Steve Bloom

Appetite regulation and obesity

Obesity is currently one of the biggest threats to the health of the nation. Food intake and energy expenditure are both tightly regulated by homeostatic mechanisms. Our exciting research employs the use of cutting edge technologies to investigate how food intake is regulated. We utilise adeno-associated virus based gene transfer to study how hypothalamic systems regulate appetite and energy expenditure. We have tested novel gut hormone analogues in animals and first into man studies are underway with the potential for development into anti-obesity therapies. Our previous Fellows have published numerous papers and many are now independent clinical academics in the UK and abroad.

Further Information:
www.hammersmithendocrinology.co.uk
http://www1.imperial.ac.uk/medicine/about/divisions/is/meta/

Contact Details
s.bloom@imperial.ac.uk
Tel: +44 (0)20 8383 3242

Maria Belvisi

Respiratory Pharmacology

Professor Belvisi heads a multidisciplinary group involved in research into cellular and molecular mechanisms of airway inflammatory disease (in particular asthma and chronic obstructive pulmonary disease) and the cough reflex. Particular emphasis has been placed on configuring appropriate disease relevant animal models and translational human and animal cell and tissue based assays. The group uses pharmacological (small molecule inhibitors and antibodies) and molecular tools to dissect signalling pathways (siRNA, Knockout mice, dominant negative technologies). Currently, there is an increased drive to translate findings into clinical studies in collaboration with several clinical centres. The research is funded by Research Councils, Charitable trusts and the Pharmaceutical Industry.

Further Information:
http://www1.imperial.ac.uk/medicine/about/divisions/nhli/respiration/
airdisease/pharmacology/

Contact Details
m.belvisi@imperial.ac.uk
Tel: +44 (0)20 7594 7828

David Brooks

Neuroimaging

(Senior Clinical Scientists - Professor DJ Brooks and Dr N Pavese)

(a) Brain MRI and water PET activation studies:
We are identifying in man the brain networks involved in motor learning, decision making, and working memory and examining the effects of reward and risk on regional brain activation. We are also examining how motor circuits adapt to the presence of basal ganglia lesions and deep brain stimulation.

(b) PET neurotransmitter binding studies:
We are using PET to study monoaminergic (dopamine, noradrenaline, serotonin) function in health and Parkinson's disease. The mechanisms underlying treatment-induced motor problems, dementia, depression, and fatigue in PD are being investigated with The mechanisms of L-dopa-induced dyskinesia, depression in PD, and idiopathic dystonia are being investigated with dopaminergic, serotonergic, substance P and adenosine A2A receptor PET tracers. The effects of neuroprotective and restorative therapies on rates of disease progression in PD are being followed. Using 11C-raclopride PET we are studying in vivo the factors (reward, learning) that determine dopamine release in health and disease.

(c) Immune response and amyloid deposition in neurodegenerative disease
We are using 11C-PK11195 PET to monitor in vivo microglial activation in Alzheimer's, Parkinson's, and other subcortical degenerations. The effects of putative neuroproective agents on microglial activity are being examined. Amyloid deposition in the dementias is being measured with 11C-PIB PET.

Further Information:
http://www1.imperial.ac.uk/medicine/people/david.brooks/

Contact Details
david.brooks@imperial.ac.uk or hyacinth.henry@imperial.ac.uk
Tel: +44 (0)20 8383 3172

Sian Harding

Stress cardiomyopathy and the b₂-adrenoceptor

Professor Harding’s laboratory has a long interest in β₂AR signalling in the failing heart. We have begun to study the increasingly recognised syndrome of Stress (Takotsubo) Cardiomyopathy where high adrenaline levels secondary to physical or emotional stress produce acute heart failure with a characteristic apical stunning. The rapid recovery of patients with this syndrome leads us to hypothesise a protective component to the underlying mechanisms (Lyon et al. Nat . Clin. Pract. Cardiovasc. Med. 5, 22-29, 2008). Of particular interest is the predominant demographic of older females, and the relation of this syndrome to other acute heart failure syndromes. Studies in the laboratory have developed a rodent model of Stress Cardiomyopathy and have started to unravel the molecular basis for the effect. These centre on the ability of adrenaline to switch the b₂AR to a cardiodepressant but protective Gi coupling. Research opportunities range from molecular biological studies targeting the b₂AR and Gi signalling pathways, influences of oestrogens and testosterone, electrophysiological and proarrhythmic consequences, cell survival paradigms, and both screening and development of novel therapeutic strategies for SCM. Many findings offer applicable insights more generally in acute heart failure syndromes. Collaboration with clinical colleagues offers integrated involvement in a proposed national clinical SCM registry, and also stress-induced sudden cardiac death registries. Screening for known b₂AR polymorphisms in the clinical population, and functional evaluation of polymorphisms uncovered upon the SCM phenotype, is one example of a potential translational clinical project.

Further Information: http://www1.imperial.ac.uk/medicine/people/sian.harding/

Contact Details
sian.harding@imperial.ac.uk
Tel: +44 (0)20 7351 8146

Dorian Haskard

Vascular disease

The main interest in Vascular Science Section is research into the regulation of gene expression in vascular endothelial cells and monocyte-macrophages in relation to the development and progression of vascular inflammatory diseases, with a particular emphasis on atherosclerosis. The group has an integrated physiological approach, with models ranging from the culture of cells under haemodynamic conditions; the use of genetically engineered mouse models; and the development of imaging strategies for measuring vascular gene expression in patients.

Further Information: http://www1.imperial.ac.uk/medicine/people/d.haskard/

Contact Details
d.haskard@imperial.ac.uk
Tel: +44 (0)20 8383 3064

David Nutt

Neuropsychopharmacology and Molecular Imaging

David J Nutt is the head of the Dept. of Neuropsychopharmacology and Molecular Imaging, a multidisciplinary grouping of clinical and preclinical scientists with the shared goal of using imaging and other translational medicine approaches to address mechanisms and treatments of brain disorders. Current research themes are PET imaging of addiction and affective disorders, pharmacological studies of sleep and anxiety and the development of new MRI approaches to explore drug effects in the brain.

Further information:

http://www1.imperial.ac.uk/departmentofmedicine/divisions/experimentalmedicine/pharmacologyandtherapeutics/psychopharmacology/

Contact Details
d.nutt@imperial.ac.uk
Tel: +44 (0)20 7594 6628

Richard Reynolds

Multiple Sclerosis

The Multiple Sclerosis Research Group is interested in understanding the pathogenetic mechanisms underlying the progressive deterioration of neurological function in MS and the role of repair processes, in particular remyelination, in preventing this progression. Our research on remyelination focuses on changes in oligodendrocyte-axon interactions that might either promote or inhibit oligodendrocyte survival and maturation. Neurodegeneration is now known to play a major role in progression and we have shown that the extent of cortical pathology provides the best correlate of irreversible disability in MS. Current studies are using post-mortem human tissue to investigate the cellular and molecular basis of the substantial neuronal damage.

Further Information: http://www1.imperial.ac.uk/medicine/people/r.reynolds/

Guy Rutter

Molecular Basis of Diabetes

All forms of diabetes involve a decline in insulin production which is absolute in Type 1 diabetes (an autoimmune disease) and relative in type 2 diabetes. We are using comparisons with simpler organisms (yeast, fruit flies etc) and the power of human genetics (eg genome wide arrays, familial linkage analysis) to identify novel approaches to improve pancreatic beta cell mass and function in type 2 diabetes. Particular current interests are in nutrient-regulated protein kinases (eg AMPK), zinc transport and Wnt signalling.

A combination of mouse molecular genetics, in vivo physiology, state-of-the-art cellular imaging (multiphoton, total internal reflection fluorescence), and electrophysiology will be deployed to develop new therapeutic strategies.

Further information: http://www1.imperial.ac.uk/medicine/people/g.rutter/

g.rutter@imperial.ac.uk
Tel: +44 (0)20 7594 3340

Michael Schneider

Cardiopoiesis: Genetic networks for cardiac muscle creation by stem cells

Adult mammalian heart muscle is characterized by a meagre ability to restore cardiac muscle cell number and pump function following cardiac muscle cell death. For this reason, cardiac muscle cell number is especially well-posed as a therapeutic target in regenerative medicine (Mercola, Ruiz-Lozano & Schneider. Genes Dev 2011; 25:299-309). Work in our laboratory is focused in part on cardiac muscle creation by embryonic stem cells, to decipher the exact genetic circuits that guide initially pluripotent cells to a cardiac muscle fate. In addition, we investigate the latent stem cells in adult cardiac muscle itself, which resemble a forme fruste of the early cardiac mesoderm seen in embryos and embryoid bodies.

Further Information: http://www1.imperial.ac.uk/medicine/people/m.d.schneider/

Contact Details

m.d.schneider@imperial.ac.uk

Tel: +44 (0)20 7594 3027

Graham Williams

Hormone regulation of bone

Osteoporosis is characterized by reduced bone mass and fracture, and represents a major public health burden affecting over 40% of women and costing the NHS £1.7 billion per annum. Bone strength and fracture susceptibility are determined by acquisition of peak bone mass during development and the rate of bone loss in adulthood. The Molecular Endocrinology Group uses state-of-the-art Cre/lox gene targeting strategies to generate mutant mouse models in which hormone signalling is disrupted in discrete bone cell lineages. We use digital X-ray analysis, dynamic histomorphometry, back-scattered electron scanning electron microscopy and laser scanning confocal microscopy, as well as molecular biological approaches, to investigate mechanisms underlying hormone control of skeletal development and bone maintenance. These studies will provide new mechanistic understanding of bone formation and bone loss that will underpin identification of novel drug targets for prevention and treatment of osteoporosis.

Further Information: http://www1.imperial.ac.uk/medicine/people/graham.williams/

Contact Details
graham.williams@imperial.ac.uk
Tel: +44 (0)208 383 1383

Oliver Howes

Psychiatric Imaging Group

Our research focuses on understanding the causes of mental illnesses and improving their treatment using PET and other functional imaging techniques.

Mental illnesses are a major cause of ill health and premature death. They account for four of the six leading causes of adult disability in the world and one in every ten hospital beds in the UK is for the treatment of psychotic disorders such as schizophrenia.

Current work in the Group is focusing on:

understanding the brain changes that lead to the development of psychotic disorders, using multi-modal imaging with PET and fMRI
examining the effects of cannabis and other drugs on the brain, and the influence of common genetic polymorphisms on brain function
determining why some patients respond to treatments and others don’t
using novel approaches to diagnosing mental illnesses
developing animal models for future drug development

Further Information: http://www.csc.mrc.ac.uk/Research/Groups/ECN/PsychiatricImaging/

Contact Details
oliver.howes@imperial.ac.uk
Tel: +44 (0)208 383 3160

Waljit Dhillo

Endocrinology - Obesity and metabolism

Endocrine function and nutritional status are tightly regulated through common pathways in order that individuals will only be able to reproduce if sufficient nutrients are available. Abnormalities in the regulation of these pathways commonly results in infertility. However the neuropeptides, hormones and neuronal circuits which regulate these important pathways remain largely unknown. Our group have recently identified novel hypothalamic regulators which are vital in the metabolic control of reproductive function. Using animal models as well as ‘first into human’ studies our work has identified the prokineticin peptides (http://www.sciencedaily.com/releases/2009/06/090610091228.htm) in the metabolic regulation of fertility and the key role of kisspeptin (http://news.bbc.co.uk/1/hi/health/7945600.stm) as a novel therapy for infertility.

Further Information: www.hammersmithendocrinology.co.uk

Contact Details
w.dhillo@imperial.ac.uk
Tel: +44 (0)20 8383 2820

Jane Mitchell

Vasoactive genes in vascular biology in the Cardiovascular System

Endothelial cells line the luminal surface of all blood vessels. Furthermore capillary endothelial cells infiltrate all organs. In this way understanding endothelial cell biology and pharmacology has implications for all types of human disease. Vasoactive genes include cyclo-oxygenase, nitric oxide synthase and endothelin-1. These genes are highly expressed in the endothelium where they work in to regulate blood flow, thrombosis, inflammation and lipid metabolism. Dysfunction of these genes leads to disease and as a consequence these genes are therapeutic targets for the treatment of cardiovascular dysfunction. Importantly inflammatory forms of cyclo-oxygeanse and nitric oxide synthase are expressed during inflammation and/or infection. The forms of vasoactive genes are regulated by pattern recognition receptors including toll like receptors (TLRs). This project seeks to investigate how endothelial cells from different origins, including stem cells, function at the cellular and whole vessel level in vitro and at the organ level in vivo and the role that vasoactive genes have in these functions.

Contact Details
j.a.mitchell@imperial.ac.uk
Tel: +44 (0)20 7351 8137

Masao Takata

Perioperative and Critical Care

Prof Takata is the head of the Section of Anaesthetics, Pain Medicine and Intensive Care, and leads a translational research group in the field of perioperative and critical care. His research team includes a number of postdocs and research students, both basic scientists and clinical trainees. The group employs a combined physiological, immunological and molecular research approach, using in vivo mouse models as the main paradigm with complementary in vitro cell biology, ex vivo isolated organ preparations and clinical patient studies. Particular emphasis is placed on the understanding of inflammatory mechanisms of the disease processes encountered in respiratory and critical care medicine, toward future clinical applications. Currently our work focuses on a) novel TNF-mediated mechanisms and therapies in acute lung injury and ventilator-induced lung injury; b) roles of monocyte-endothelial interactions in lung injury and sepsis-associated organ injury; and 3) clinical studies investigating cytokine biology and monocyte function in post-operative and ICU patients.

Further information: http://www1.imperial.ac.uk/surgeryandcancer/divisionofsurgery/apmic/

Contact Details
m.takata@imperial.ac.uk
Tel: +44 (0)20 8383 3789