About the Project
Skeletal muscle is a major and important component of the mammalian body and the consequences of loss of control of the regulatory factors which govern skeletal muscle development can be fatal. One example is the serious heritable disease of Duchenne muscular dystrophy (DMD), but muscle atrophy is also a serious problem of old age. Using cultured stem cell models we have shown that dystrophic muscles undergo excessive cycles of cell death (apoptosis) and proliferation and have also shown that the growth factor (Igf-2) can modify this. We are now investigating the mechanisms by which IGF-2 exerts this control by examining both developing and ageing muscles as well as those with diseases such as DMD. To develop strategies for gene therapy of skeletal muscle diseases such as DMD we have developed an in vivo/in vitro stem cell model which is capable of delivering potentially curative genes (such as Igf-2) directly into target skeletal muscles. More recently we have begun to dissect the molecular pathway that regulates skeletal muscle cell death or survival and have identified one gene (PKB/pAkt) which plays a pivotal role in this pathway. Using a range of biochemical, molecular biology, genetic, cell and whole animal techniques (including the relatively new techniques of RNA silencing and microarray analysis) we are investigating the function of this pathway and why it is perturbed in muscular dystrophy (MD) as well as identifying potential (pro and anti-apoptotic) target genes that may be used to develop therapies to treat MD. Current projects include projects to analyse signal transduction pathways in MD and in the embryogenesis of skeletal muscle disease.
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Please find additional funding text below. For further funding details, please see the ‘Funding’ section.
The School of Biosciences offers a number of UK Research Council (e.g. BBSRC, NERC) PhD studentships each year. Fully funded research council studentships are normally only available to UK nationals (or EU nationals resident in the UK) but part-funded studentships may be available to EU applicants resident outside of the UK. The deadline for applications for research council studentships is 31 January each year.
Each year we also have a number of fully funded Darwin Trust Scholarships. These are provided by the Darwin Trust of Edinburgh and are for non-UK students wishing to undertake a PhD in the general area of Molecular Microbiology. The deadline for this scheme is also 31 January each year.
References
Rao A., O’Shea L., Toora M. & Smith J. An accelerated model of skeletal muscle atrophy: regeneration and adipogenesis precede atrophy. (Submitted)
Smith, J. & Merrick, D (2008). Embryonic skeletal muscle micro-explant culture and isolation of skeletal muscle stem cells. In// Methods in Molecular Biology: Mouse Cell Culture. Editors A. Ward & D. Tosh. Humana Press, in press
D. Merrick, Tao Ting, L.K.J Stadler, J. Smith (2007). A role for Insulin-like growth factor 2 in specification of the fast skeletal muscle fibre. BMC Developmental Biology 7:65
Toora, M., Merrick, D., Rao, A. & Smith, J. (2003). “Stem cells, skeletal muscle and the mammalian ageing process”. Proc. Indian Natn. Sci. Acad. B69: 191-208.
D. Merrick, I Badr, M Watkins, J. Smith. (2002). IGF-2 function in skeletal muscle differentiation. Edited by AJ Copp & EMC Fisher. Genet. Res. Camb. 80, 63-75.
Wesbury J, Watkins M, Ferguson-Smith AC, and Smith, J. (2001). Dynamic and temporal regulation of the cdk inhibitor P57kip2 during embryo morphogenesis. Mechanisms of Development 109: 83-89.
L. C. O’Shea, C. Johnson, M. Rooney, R. Gleeson, K. Woods & J. Smith (2001) Adipogenesis and skeletal muscle ageing Mech. Ageing Devel. 122, 1354-5.
Smith, J, Goldsmith, C, Ward, A & LeDieu, R (2000) IGF-II ameliorates the dystrophic phenotype and coordinately down-regulates programmed cell death. Cell Death and Diff. 7, 1109-1118.
Grandjean, V, Smith, J, Watkins, M & Ferguson-Smith, A.C. (2000). Increased IGF-II protein affects P57kip2 expression in vivo and in vitro: implications for Beckwith-Weidemann syndrome. Proc. Natl. Acad. Sci. (USA) 97, 5279-5284.
Woods, K., Marrone, A. & Smith, J (2000) Programmed cell death and senescence in skeletal muscle stem cells. Ann. Proc. Natl. Acad. Sci 908, 331-335.
Smith J & Schofield P N (1997) Cell Growth Differ 8, 927-934 Smith J (1996) Br Appl Myol 6, 279-284
Smith J et al (1995) Cell Death Differ 2, 243-251
Smith J & Schofield P N (1994) Exp Cell Res 210, 86-93
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