The Department of Investigative Medicine focuses on intercellular regulatory systems and the way in which they are disturbed in human disease. The Unit has developed international expertise in the measurement synthesis and actions of regulatory peptides and applies this knowledge particularly to the study of hypothalamic, pituitary and islet of Langerhans function. Thus particular attention is paid to reproductive dysfunction, the effects of stress, mechanisms regulating appetite, metabolism and the major disease there of, diabetes mellitus.
The Unit has been highly successful over the last year with a number of original observations throwing new light on the way the systems function. Grant funding has increased and the groups plan to focus activities on the 6th floor laboratories of the Commonwealth Building has been successfully completed. The exciting new basic science developments consequent, on the fusion of several medical schools to form the Faculty of Medicine of Imperial College London, offer exciting opportunities for future advance.
The department has extensive research facilities, including a full range of cell and molecular biology laboratories, and the laboratory is internationally renowned for its work on gut hormones, carbohydrate metabolism, hypothalamic control mechanisms and regulation of cell growth.
The department has two main sections. One provides the routine clinical chemistry for the Hammersmith Hospitals Trust and the other concentrates on research and teaching. The department works closely with the Endocrinology Unit within the Department of Medicine, sharing a director and several other posts. This offers the opportunity for staff and students to help to provide a clinical service and, if appropriate, be taught clinical skills at the bedside. The Department contributes to both undergraduate and postgraduate medical education within the Faculty of Medicine of Imperial College London.
Current research student projects include human service antigen known as OX 47, and regulation of transcription of the human calbindin D9K gene.
The Department has considerable research strengths. It currently has 15 clinical research fellows (of which 15 are registered for PhDs) and 9 PhD studentships. It has a high publication rate in prestigious international journals and these articles are very highly cited (in the 1980-89 period the laboratory was the most highly cited in Europe). The laboratory is internationally known for its work on gut hormones, carbohydrate metabolism, hypothalamic control mechanisms and regulation of cell growth.
The focus for research is on intercellular regulatory systems and the way in which they are disturbed in human disease. The Unit has developed international expertise in the measurement, synthesis and actions of regulatory peptides and applies this knowledge particularly to the study of hypothalamic, pituitary and islet of Langerhans function. Particular attention is paid to reproductive dysfunction, the effects of stress, mechanisms regulating appetite, metabolism and the major disease there of, diabetes mellitus.
The Department is currently divided into several research groupings with the endocrine group consisting of the largest number of scientists. There are several smaller groups as well.
1. Hypothalamic control of energy balance
It has been an exciting year in the field of hypothalamic control of food intake. This department has been at the forefront of research in this area, with publications on the role of hypothalamic melanocortin agonists and antagonists, melanin concentrating hormone (MCH), the orexins, cocaine and amphetamine regulated transcript (CART) and glucagon like peptide-1 (GLP-1). As energy balance is dependent on the maintenance of an equilibrium between food intake and energy expenditure, the department has expanded its research area to encompass control of energy expenditure. The current main focus on the hypothalamic control of the thyroid axis and thermogenesis by melanocortin agonists and antagonists. (Bloom, Ghatei, Smith, Meeran, Dornhorst, Mitchell).
Hypothalamic control of reproduction
Control of the hypothalamo-pituitary-gonadal (H-P-G) axis is a major function of the hypothalamus, and a number of peptides have been implicated in this system. Hypothalamic peptides that alter food intake also influence reproductive function and may control nutritional infertility. During the last year, we have demonstrated that the melanocortin antagonist AgRP is a potent stimulant of the H-P-G axis. We have also demonstrated that receptors for neuromedin U are affected by gonadal-steroid hormone environment. Work in progress in this area includes further investigation of the role of the melanocortin system and novel research on the importance of Prolactin Releasing Peptide (PrRP) and CART.
The Hypothalamus and the Stress Axis
The raft of physiological responses to stress are vital for life, and the hypothalamus plays a crucial role in co-ordinating these. We have previously played a major role in characterising the involvement of neuropeptide Y (NPY) in this axis, and these investigations have continued this year. We have also demonstrated that the melanocortins and CART play an important role in the activation of the hypothalamo-pituitary adrenal axis.
2. Carbohydrate Control Mechanisms
Attention is focused on the pro-glucagon peptide, GLP1 and its reptile equivalent, exendin. These have been demonstrated to have a potent effect on the islet and offer the prospect of a new form of therapy for type II diabetes.
3. CGRP and adrenomedullin receptors
CGRP and adrenomedullin are two powerful vasodilator peptides with different pharmacology and a number of possible roles in vascular and endocrine pathophysiology. Their potential as therapeutics has been untapped due to the lack of target receptors. CRLR, a G-protein coupled receptor cloned in this department, has been shown to be a receptor for both peptides. The different pharmacologies of the two peptides are obtained by co-expression of proteins called RAMPs. This exciting development is currently being investigated in the receptor laboratory, in particular the properties of stably transfected cells expressing CRLR and RAMPs 1,2 or 3. These cells are being investigated with respect to their ligand binding, signal transduction pathways and receptor desensitisation.
4. Insulin Resistance
This group is looking into the field of insulin resistance. Exploration of the role of the adipocyte in determining insulin resistance and cardiovascular risk factors. I collaboration with the Department of Dietetics & Nutrition, the way in which dietary carbohydrates influence and modify insulin resistance are being looked at. A new study is to commence shortly study examining how pregnancy effects insulin sensitivity at different adipocyte sites, and what lasting influences first and subsequent pregnancies have on insulin sensitivity and body fat distribution.
5. Cytochemistry, Cardiovascular Risk Factors & Clinical Collaboration
The academic department of Chemical Pathology at Charing Cross campus has research activity in three areas.
Firstly, using cytochemical techniques, it is involved in three projects:
1. Birefringence (as a measure of muscle viability) in human muscle from elderly patients;
2. Prevention of osteoarthritis
3. Metabolism of gastrointestinal tumours with particular reference to redox state, pentose shunt and Kreb’s cycle, in cancer cells.
Secondly, there is an interest in cardiovascular risk factors and using markers; homocysteine, allantoine and LP(a). The department is collaborating with the Renal Unit to elucidate the involvement of these risk factors in patients with renal failure.
Thirdly, the department is involved in various clinical research work with other departments;
1. With the Department of Obstetrics and Gynaecology at Chelsea & Westminster Hospital in looking at bone turnover markers in patients with osteoporosis and the effect of HRT.
2. Within Investigative Medicine we are looking at non-invasive pituitary function tests.
6. Local regulation of bone metabolism and the molecular basis of steroid-induced and post-menopausal osteoporosis.
7. Cell Transformation Laboratory
To replicate their genome in the normally quiescent cells of an organism, most DNA viruses encode a protein that stimulates the cell into cycle. Consequently, when expressed outside a normal viral lytic cycle, these proteins are potentially tumorigenic. The Cell Transformation laboratory makes use of these proteins to determine how the cell cycle can be deregulated during cancer development. This is an important prerequisite to the design of strategies to reverse this process.
In particular, the group is currently examining the actions of the potent oncogene middle T-antigen (MT) encoded by the polyoma virus. Over the last few years, we have demonstrated that MT acts as an analogue of an activated growth factor receptor, so we have been able to use MT as a tool to examine how the signalling pathways used by such receptors stimulate growth under normal, and pathogenic conditions. In the last year, we have unravelled some of the signalling pathways involving the oncogene Shc, made progress in determining how the pp60c-src proto-oncogene product is regulated, examined the regulation and role of protein phosphatase 2A in cell cycle control, and finally, started to determine how the membrane location of MT is established and the role this has on signal transduction. In the future, this work will be continued to define how these signalling pathways function normally and abnormally, and new functions for MT will be sought.
8. Toxicology Unit, Charing Cross Campus
The Toxicology Unit provides analysis and toxicological expertise to HM Coroners throughout London and the South of England handling in excess of 1000 cases per year. It also performs analysis of urine for drugs of abuse for various mental health teams in the West of London. It has extensive experience of the analysis of biological fluids for drugs and in the interpretation of the results. The research of the Toxicology Unit is focused on exploiting the experience, the expertise and the uniqueness of the unit in the analysis of urine and hair for drugs of abuse.
· To contribute to the field of forensic toxicology
· To use our experience and expertise to solve forensic/clinical problems
· Development of a cost-effective method using the powerful technique of gas chromatography/mass spectrometry for routine analysis of urine from drug treatment patients.
· Development of a method for the simultaneous analysis of 18 drugs of abuse/metabolites from one 50 mg sample of hair.
· The method has been used to study the inter-individual dose/concentration relationship for methadone in hair. A follow-up study looking at intra-individual dose/concentration for methadone is on-going.
· Analysis of hair from addict related deaths is being carried out to investigate if there is any relationship between a person’s drug history and the fatal blood concentration of drug.
· The technique has been employed in various collaborative studies including:
a) Covert substance misuse among out patients receiving methadone-maintenance at a central London drug-dependency unit. (Completed)
b) A study of co-morbidity of substance misuse and mental illness. (Completed)
c) A longitudinal study of the possible effects of recreational drugs (esp. MDMA) on infants exposed to such substances in utero. (On-going)
The Department also undertakes research in collaboration with the Divisions of Neuroscience, and Medicine, and with the Pharmocology Department at Cambridge University.
The Department is strongly committed to the Divisional aim of developing the new Undergraduate Curriculum and delivering courses which are challenging, innovative and stimulating, within the financial framework operated by the College.
Professor Karim Meeran (who last year was awarded ICSM "Teacher of the Year") runs the MRCP Part 2 courses in conjunction with the Division of Medicine.
Division of Investigative Science
Imperial College London, Hammersmith Campus, Commonwealth Building, Du Cane Road
London, W12 0NN
Tel: 44 (0) 20 8383 3242
Fax: 44 (0) 20 8383 3142
Email: Professor Steve Bloom