Current Research Projects
i) Systems biology and control engineering approach to beta cell mass regulation in vivo.
Collaborative project with Andy Chipperfield, Southampton University and Will Heath, Manchester University.
Diabetes, characterised by an insufficient number of beta-cells in the pancreas, leads to the loss of blood glucose regulation and, if left untreated, complications such as heart disease, blindness and kidney damage will occur with devestating consequences. Diabetes currently affects over 2,000,000 people in the UK alone and this number is steadily increasing. Since the discovery of insulin in 1921 there has be a steady progress in treatment of the disease but none that have been able to address the shortfall in beta-cells or arrest their decline in number. The complexity and cost of investigating therapeutic targets is a significant hurdle to the development of new treatments or a cure. It is also one of the main motivations for attempting to develop computational models that can be used to predict and explain the processes governing the regulation of the number of functioning beta-cells in the pancreas. The aim of this work is to bring together researchers from control systems engineering and biological science to work in each others' laboratories towards developing such models. In particular, this research will apply appropriate methodologies from control systems engineering to the analysis of the biological problem at a number of different levels from data collection and error analysis to process and network modelling. The combination of researchers and their shared use of facilities will enable a deeper understanding of the requirements and constraints of the problems, the nature of measurable parameters and potential signalling and process structures. This should enable more biologically meaningful models to be constructed that in turn can be used to drive the experimental process in a targeted manner. While the work here considers the problem of beta-cell homeostasis, we fully expect the results of this research to have wider significance in systems biology and elsewhere.
ii). Use of conditional mutagenesis in the development of cell lines.
Dr. Stella Pelengaris, a research fellow in this unit, has developed a regulatable transgenic system allowing ectopic activation of c-Myc protein in adult tissues (Pelengaris SA, Littlewood T, Khan M, Elia G and Evan G. Reversible activation of c-Myc in skin-induction of a complex neoplastic phenotype by a single oncogenic lesion. (1999). Molecular Cell 6: 565-577; Pelengaris, S*., Khan, M*., and Evan, G. Suppression of Myc-induced apoptosis in beta cells exposes multiple innate oncogenic properties of Myc sufficient to trigger immediate carcinogenic progression (2002). Cell, 109(3): 321-334). A similar system has now been targeted to beta-cells and is being used to develop beta-cell lines with potential use in transplantation. In existing beta-cell lines the ability to expand cells in vitro is achieved at the expense of vital differentiated functions. Such cell lines lose the ability to secrete insulin appropriately in response to glucose, and could not therefore be used in cell therapy for diabetes. The unique regulatable c-Myc system, however, will allow us to expand cultures by activating c-Myc, and importantly by subsequently de-activating c-Myc restore normal differentiated function. We believe that this approach may finally allow the realisation of a major goal in diabetes research; the development of a readily expandible cell-line retaining fuel-dependent insulin secretion.
iii). Regulation of beta-cell apoptosis in vivo: role of Myc in the pathogenesis of diabetes and in islet neoplasia.
Many proteins with mitogenic potential also induce apoptosis. Although, this dual potential may provide protection against growth deregulation and cancer, it could also contribute to the development of degenerative diseases. The proto-oncogene c-Myc is involved in beta-cell proliferation and, as we have recently shown, in beta-cell apoptosis. During the development of human type 2 diabetes, beta-cells are initially expanded to cope with increasing demands for insulin secretion, but as the disease progresses beta-cell numbers wain. We are investigating the potential dual role of c-Myc in regulating both proliferation and subsequently apoptosis of beta-cells in vivo.
We are also collaborating with Professor Gerard Evan (UCSF) in the study of oncogene co-operation with c-Myc in the development of cancer.
iv) Islet regeneration. We are investigating the early events following islet loss and in particular developing temporal maps of gene/protein expression during islet regeneration in vivo.
v) We are using microarray and proteomics to identify Myc-target genes specifically involved in the opposing (but at least in part coupled) processes of Myc-induced growth or apoptosis. To analyse these complex time sries data we are part of a large systems biology metwork at the University of Warwick- see also www2.warwick.ac.uk/fac/sci/systemsbiology/ipcr/
vi). The role of sterol metabolism and lipoprotein modification in apoptosis; mechanisms for chronic inflammation in atherosclerosis.
Chronic inflammation within the artery provokes the development of atherosclerosis and eventually the destabilisation of lesions underlying myocardial infarction and stroke. Yet, little is currently known about the processes responsible for maintaining inflammation in the atherosclerotic artery. We are using in vitro models of atherosclerosis to study the interaction between apoptotic vascular smooth muscle cells and macrophage/monocytes in the generation of inflammation.