Research projects
Current projects
Regenerative mechanisms in heart and skeletal muscle
Our laboratory focuses on regenerative biology, which explores the processes that restore the architecture of damaged or degenerating tissues, often by recapitulating original embryonic development. We aim to reduce the impediments to effective regeneration by recapturing the remarkable regenerative capacity of lower vertebrates. Using the mouse to define the mechanisms involved in the mammalian response to injury, disease and ageing, we are identifying and modulating key signalling pathways that induce the recruitment of progenitor cells to sites of tissue damage and augment local repair mechanisms.
IGF and regeneration
We found that insulin-like growth factors attenuate muscle atrophy and improve repair in ageing, muscular dystrophy and cardiomyopathies. Delivery of an unprocessed IGF-1 isoform (mIGF-1) to various neuromuscular pathologies implicate this growth factor as a powerful enhancer of there generation response. Selective muscle fibre loss and fibrosis in ageing and diseased skeletal muscle can be blocked by transgenic or viral delivery of mIGF-1, which augments local repair mechanisms and promotes recruitment of stem cells to sites of injury. Supplemental mIGF-1 expression reduces specific inflammatory cytokines, suggesting that improvement both skeletal and cardiac regeneration operates in part by modulation of the inflammatory response. In collaboration with the Nerlov lab we have explored the role of the innate immune system in the regeneration process, linking the pathways leading to macrophage polarisation and effective tissue repair.
Heart regeneration
In the heart, supplemental mIGF-1 expression increases progenitor cell pools, induced new signalling pathways and results in complete cardiac repair after myocardial infarction with minimal scar formation. We are currently exploring the signals in the epicardium, the outer cell layer of the heart, which may contribute to improved regenerative response. More recently, we have extended our studies of regeneration to the skin, where supplemental mIGF-1 expression improves wound healing and accelerates hair follicle formation and cycling.
Expression of IGF-1 isoforms in vivo has allowed us to assign specific functions of different peptide domains in muscle hypertrophy and regeneration. The different responses evoked by various IGF-1 isoforms suggest specific mechanisms through which combinations of supplemental growth factors can improve regeneration, providing new targets for clinical intervention. Further studies in skeletal and cardiac muscle have implicated NFκB, calcineurin and Notch-mediated signalling pathways in the intervention of tissue damage and disease.
Genes and development
In a new project we have extended our studies of cell signalling in development to address the role of a Fibroblast Growth Factor decoy receptor FGFRL1 in embryonic patterning. FGFRL1null mice present multiple dysmorphologies reminiscent of human Wolf-Hirschhorn syndrome, implicating the decoy receptor in the etiology of this congenital disease.
Future projects and goals
In our future research, we will harness conditional and inducible mouse genetics to characterise key mechanisms implicated in the regenerative response. We will characterise the molecular action of growth factors and their intracellular intermediates to identify further candidates for therapeutic application. Our studies are designed to define the common nodal points of signaling in mammalian regenerative processes as they relate to embryonic development. At the cellular level, we are particularly interested in the role played by myeloid cell lineages in controlling inflammation and promoting tissue repair. We hope to use this knowledge for developing clinically relevant interventions in ageing, injury and degenerative disease.