Institute of Nephrology, Cardiff University
029 2074 8390
029 2074 8470
Relevant Key Words:
Fibroblasts, Growth factors, Inflammation, Proteoglycans, Hyaluronan, Fibrosis, Extracellular Matrix
Research Expertise relevant to tissue engineering & repair:
My research is focussed on the biology of the myofibroblast, the cell that mediates scarring and fibrosis in most organs. In the kidney their appearance at biopsy is the earliest marker of progressive disease. We were the first group to characterise normal fibroblasts and myofibroblasts from human renal cortex. We have subsequently described changes in the synthesis of selected extracellular matrix components as fibroblasts differentiate into myofibroblasts. Specifically, we have shown, for the first time, changes in proteoglycan and hyaluronan synthesis that accompany this differentiation and which alter the repertoire of growth factor responses of the cells. We are currently investigating the exact structural changes in the glycosaminoglycan chains that mediate this in collaboration with Professors John Gallagher and Malcolm Lyon, Christie Hospital, Manchester, UK. and Professor Ann Woods, Department of Cell Biology and Anatomy, University of Alabama at Birmingham, AL, USA. In collaboration with Professor Tony DayProfessor Robert Stern, University of California, San Fransisco, Dr Dusty Miller, Fred Hutchinson Cancer Research Center, Seattle and Professor Bryan Toole, University of South Carolina, Charleston, USA, we are also investigating whether the accumulation of an expanded hyaluronan matrix affects the pro-fibrotic responses of the cells to TGF, while with Professor David Thomas and Dr Phil Stephens, Wound Biology Group, School of Dentistry, Cardiff University, we have projects investigating the potential association of hyaluronan with scar-free healing and with age-related alterations in cell function. Moreover, the structure of hyaluronan is modified by specific binding proteins which we believe control its functional interaction with cells. With Professor Tony Day, University of Manchester we are examining the detailed role of one of these, TSG-6, in controlling cell responses to hyaluronan.
While matrix accumulation is a major focus of our studies, we also have a long-established interest in its degradation and turnover, specifically the role of metalloproteinases, and the subsequent effect on cell function. We have described recently, for example, the essential role of the disintegrin/metalloproteinase ADAM15 in controlling mesangial cell migration. This molecule is constitutively expressed in these cells and we are currently investigating its transcriptional and translational control in more detail. The ADAM15 knock out mouse has no kidney phenotype. In collaboration with Dr Carl Blobel, Memorial Sloan-Kettering Cancer Center, New York and Dr Jeffrey Kopp, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, however, we are investigating whether the knock out of ADAM15 affects mesangial remodelling or scarring in a model of progressive glomerular disease.
Although changes in extracellular matrix are important in modulating cell function, we have also shown that renal (and other) fibroblasts alter their phenotype during interactions with inflammatory cells. We demonstrated that renal fibroblasts expressed the adhesion molecules ICAM-1 and VCAM-1 and that when either of these molecules was ligated by leukocytes, it induced the expression of the other. Ligation triggered intracellular signalling and we were the first group to show that part of the ICAM-1 signalling mechanism involves triggering a rise in the intracellular calcium ion concentration, leading to NFkB and AP-1 transcription factor activation. In collaboration with Dr Aled Clayton, Section of Clinical Oncology, we have described the importance of leukocyte-derived exosomes in this process. We are currently investigating this in more detail and applying these observations to cell types relevant to other chronic diseases.
If you have reagents that may be of interest to the CITER Membership, e.g. cell lines, microbiological cultures. Please give a representative list below:
Many molecular biology reagents (siRNA, reporter constructs and overexpression vectors) for components of the hyaluronan metabolic and catabolic pathways.
Microscopic expertise: - 4 microscopes with fluorescence (1 three-colour and 2 with time lapse facility).