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Muscle ageing and gene expression balance in Caenorhabditis elegans.

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  • Full or part time
    Prof I A Hope
    Dr M-A Shaw
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Background: Sarcopenia, or muscle ageing, is the major factor in mobility decline in older people and of increasing concern with our ageing population. A link between impairment in excitation-contraction coupling and muscle ageing has been proposed repeatedly, suggesting excitation-contraction coupling is an important target through which medical interventions might be applied to delay human muscle ageing. Cellular calcium ion homeostasis depends on a large number of interacting proteins regulating the calcium ion channels in the sarcoplasmic reticulum membrane. Sub-optimal regulation of calcium homeostasis, perhaps exacerbated by protein level changes with age due to the reduced strength of natural selection in post-reproductive animals, does contribute to muscle ageing. Ageing, however, is most easily studied in short-lived, experimentally tractable species like the nematode Caenorhabditis elegans and muscle-ageing is readily followed in living C. elegans using myosin::GFP fusions to reveal the integrity of the sarcomere. The remarkable level of conservation that exists across the animal kingdom at the molecular genetic level, as emphasized by genomic analyses over the last few decades, means discoveries made in this experimentally tractable system are usually directly relevant to human biology.
Objectives: Expression levels of genes for different components of the calcium ion channel regulatory system in C. elegans body wall muscle cells will be modified, both subtly and more dramatically, and the consequences for muscle ageing will be measured, by for example epifluorescence microscopy. The modifications will be achieved using the CRISPR-Cas9 technology. While most such manipulations are likely to accelerate muscle ageing, those that delay muscle ageing even slightly will reveal targets for further study. More comprehensive variation in expression levels of these targets at different points through the lifespan will reveal the degree of significance different levels of that protein have for muscle ageing. The significance of changes in expression levels for orthologues of these targets for human muscle ageing will then be assessed using clinical samples. This will involve a collaboration with the world-leading national referral centre for malignant hyperthermia also based in Leeds. The genetic basis for malignant hyperthermia lies in skeletal muscle excitation-contraction coupling with links to various other clinical conditions and human muscle ageing.
Novelty: While muscle ageing has been studied in C. elegans, the significance of expression levels of components of the calcium ion channel regulatory system for muscle ageing has not been investigated previously.
Timeliness: The recently developed CRISPR-Cas9 based genome editing technology makes precise alterations of the C. elegans genome facile. Precise and subtle alterations in the promoter regions of genes make controlled alteration of gene expression levels straightforward in this important model system. All the experimental advantages of C. elegans allow for rapid progress and permit experience of a wide range of experimental techniques and approaches within a PhD project.



Funding Notes

4 year BBSRC studentship, under the White Rose Mechanistic Biology DTP.  The successful applicant will receive fees and stipend (c.£13863 for 2014-15). The PhD will start in Oct 2015.  Applicants should have, or be expecting to receive, at least a 2.1 Hons degree in a relevant subject.  EU candidates must have been resident in the UK for 3 years in order to receive full support.  There are 2 stages to the application process.  Please see our website for more information:
www.fbs.leeds.ac.uk/gradschool/keywords/mnuFindaphd.php

References

Savory F.R., Benton T.G., Varma V. , Hope I.A. and Sait S.M. (2014) Ecol. Evol., 4, 1176-85. “Stressful environments can indirectly select for increased longevity.”

Craig H.L.,Wirtz J., Bamps S., Dolphin C.T. and Hope I.A. (2013) BMC Genomics, 14, 249. “The significance of alternative transcripts for Caenorhabditis elegans transcription factor genes, based on expression pattern analysis.”

Feng H. and Hope I.A. (2013) Genesis: The Journal of Genetics and Development, 51, 163-78. “The Caenorhabditis elegans homeobox gene ceh-19 is required for MC motorneuron function.”

Boyle J.H., Berri S.,Tassieri M., Hope I.A. and Cohen N. (2011) Frontiers in Behavioral Neuroscience, 5, 10. “Gait modulation in C. elegans: It’s not a choice, it’s a reflex!”

Savory, F.R. Sait S.M. and Hope I.A. (2011) PLoS One, 6 (9), e24550. “DAF-16 and Δ9 Desaturase Genes Promote Cold Tolerance in Long-Lived Caenorhabditis elegans age-1 Mutants.”

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