Molecular Basis of Neuronal Ageing
Start date: 01 May 2009,
End date: 30 Apr 2015
Ageing is associated with marked decrease of neuronal function and increased susceptibility to neurodegeneration, in organisms as diverse as the lowly worm Caenorhabditis elegans and humans. Although, age-related deterioration of the nervous system is a universal phenomenon, its cellular and molecular underpinnings remain obscure. What mechanisms are responsible for the detrimental effects of ageing on neuronal function? The aim of the proposed research programme is to address this fundamental problem. We will implement an interdisciplinary approach, combining the power of C. elegans, a highly malleable genetic model which offers a precisely defined nervous system, with state-of-the-art microfluidics and optical imaging technologies, to manipulate and monitor neuronal activity during ageing, in vivo. Our objectives are four-fold. First, develop a microfluidics platform for high-throughput manipulation and imaging of specific neurons in individual animals, in vivo. Second, use the platform to monitor neuronal function during ageing in isogenic populations of wild type animals, long-lived mutants and animals under caloric restriction, a condition known to extend lifespan from yeast to primates. Third, examine how ageing modulates susceptibility to neuronal damage in nematode models of human neurodegenerative disorders. Fourth, conduct both forward and reverse genetic screens for modifiers of resistance to ageing-inflicted neuronal function decline. We will seek to identify and thoroughly characterize genes and molecular pathways involved in neuron deterioration during ageing. Ultimately, we will investigate the functional conservation of key isolated factors in more complex ageing models such as Drosophila and the mouse. Together, these studies will lead to an unprecedented understanding of age-related breakdown of neuronal function and will provide critical insights with broad relevance to human health and quality of life.
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