Network biology approaches reveal a link between ribosome biogenesis and metabolic reprogramming in ageing skeletal muscles

Clarke, Kim (2014). Network biology approaches reveal a link between ribosome biogenesis and metabolic reprogramming in ageing skeletal muscles. University of Birmingham. Ph.D.

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Abstract

The prevalence of muscle dysfunction in elderly populations represents a significant burden on healthcare due to the increased risk of injury, and difficulty in maintaining activities of daily living. This thesis describes the application of advanced computational techniques designed to “learn” the structure of molecular networks to understanding human skeletal muscle ageing. Using this approach we have been able to discover a link between protein translation and age-dependent metabolic reprogramming. Experimental validation using the haploinsufficient eukaryotic initiation factor 6 (eIF6) mouse confirmed this important hypothesis and revealed a substantial molecular reprogramming. The role of eIF6 in skeletal muscle and myoblasts was further investigated, revealing potential up and down-stream signalling mechanisms.
The process of angiogenesis is an important step in morphogenesis including systems as diverse as muscle regeneration and tumour growth. This thesis presents the first temporal model of transcriptional alterations in tumour and the surrounding stroma during vascularisation. The application of reverse engineering approaches that are able to integrate perturbation data lead to the hypothesis that modulation of the pro-inflammatory cytokine IL1α may be an important upstream event in angiogenesis

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):