Dr Dipak Ramji
Photos of coronary arteries.
The overall aim of research in my laboratory is to understand comprehensively how specific factors, such as cytokines and lipid metabolites, regulate gene expression during health and disease. In particular, we are elucidating the pathways leading from the interaction of such factors with their receptors, through the intracellular signalling cascades, to the control of gene expression in the nucleus. Specific focus is on cytokine signalling and gene expression, particularly in macrophages, in inflammatory disorders such as atherosclerosis, with the longer-term goal of identifying new therapeutic/preventative targets/avenues. Previous and current research has been funded by grants from the Wellcome Trust, BBSRC, British Heart Foundation, MRC and GlaxoSmithKline. Our research is focused on two major areas:
Regulation of macrophage gene expression during atherosclerosis
Drawing of molecular structure.
Atherosclerosis and its complications, such as coronary heart disease and stroke, are directly responsible for about 34% of all deaths in the Western world. Atherosclerosis is an inflammatory disorder of the vasculature orchestrated by cytokines. Macrophages play a prominent role in the pathogenesis of this disease, with the uncontrolled uptake of atherogenic lipoproteins by these cells and the subsequent transformation into foam cells representing a critical early step in atherogenesis. The products of several genes contribute, either directly or indirectly, to the inflammatory response, lipoprotein metabolism and foam cell formation. The regulation of such genes by factors that are known to be present in the atherosclerotic lesion, such as cytokines, growth factors, chemotactic factors and modified lipoproteins is, therefore, likely to make a major contribution to the initiation and the progression of the disease. A major focus of research in my laboratory is devoted to understanding the molecular mechanisms by which such factors, particularly cytokines, regulate the inflammatory response, foam cell formation and the expression of key genes implicated in these processes. Specific focus is on the actions of interferon-gamma, transforming growth factor-beta and interleukin-33. In addition, the mechanisms underlying the anti-inflammatory actions of drugs (e.g. statins, activators of nuclear receptors) and fatty acids/metabolites (e.g. dihomo-gamma-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid) are being elucidated. Such studies will advance our understanding of the molecular basis of foam cell formation and atherosclerosis and, in the longer term, identify potentially novel targets for therapeutic intervention.
The development of an atherosclerotic lesion
Regulation of transcription factors belonging to the CCAAT/enhancer binding protein (C/EBP) family
Regulation of transcription factors belonging to the CCAAT/enhancer binding protein (C/EBP) family.
The C/EBP family plays a key role in the control of cellular growth and differentiation, and the pathogenesis of several diseases. The regulation of these factors during both physiological and pathophysiological conditions has hitherto been poorly understood. The regulation of the C/EBP family during inflammation in the liver was the focus of my post-doctoral research and has been continued at Cardiff. In addition, several projects have been initiated to delineate the mechanisms by which cytokines regulate the expression of the C/EBP family during a number of other inflammatory conditions.
British Heart Foundation
Prof. Foo Liew (FRS), University of Glasgow
Prof. Thomas Decker, Max F. Perutz Laboratories, Vienna
Prof. Masato Ogata, Mie University Graduate School of Medicine
Drs Jacques Pouysségur and Giles Pàges, University of Nice
Prof. Sammy Boussiba and Dr. Inna Khozin-Goldberg, Ben-Gurion University
Dr. Daryn Michael, Cultech Ltd
Dr Jason Johnson (Bristol Heart Institute)
Prof. Jonathan Napier and Dr. Olga Sayanova, Rothamsted Research
Dr. Nigel Pearce, GlaxoSmithKline
Prof. Gavin Wilkinson, and Drs Timothy Hughes, John Martin, Tim Bowen, Eddie Wang and Ian Humphreys, School of Medicine, Cardiff
Diagram of regulation of macrophage gene expression.