Regulation of stress-responses and ageing by mitochondria-to-nuclear signalling (in collaboration with Gino Poulin’s group)
Ageing occurs by the accumulation of damage to cells leading to progressive deterioration of physiological functions. It is influenced by both genetic and environmental factors. Importantly, genetic manipulations that slow ageing can also delay the onset of many diseases such as cancer and those associated with neuronal and muscle degeneration. Therefore, targeting the molecular basis of ageing may also protect from ageing-related disease. The signalling pathways that regulate lifespan are often associated with the cellular response to stress or nutrients. Mitochondrial function is sensitive to both and mutations in a number of genes encoding mitochondrial proteins affect lifespan. Our research has uncovered a novel evolutionarily conserved route of communication between mitochondria and nuclei that is sensitive to reactive oxygen species and regulates the expression of stress-response genes. Furthermore, perturbation of this pathway modulates lifespan in both C. elegans and mice. We are investigating how changes in the transcriptional network in response to mitochondrial signalling controls ageing and also determining the molecular mechanisms underlying ROS-mediated regulation of this pathway. This research will enhance our understanding of how perturbation of mitochondrial communication with nuclei contributes to ageing and ageing-related diseases.
Determination of cell fate by regulators of the TOR signalling pathway
To survive and grow, cells and organisms must coordinate their metabolism with changes in their environment. The TOR signalling pathway is a master regulator of metabolism and growth that responds to growth factors, stress and nutrients. It is implicated in diseases including cancer, diabetes, and obesity, making it an attractive target for therapeutic intervention. The TOR protein kinase is at the centre of a network and forms two discrete complexes (TORC1 and TORC2) that are differentially regulated and target distinct sets of substrates. We have identified novel regulators of TOR signaling and we are currently characterising how these proteins modulate specific TOR functions, including cell size and the cell cycle. This work will contribute to our understanding of how a key signalling pathway integrates multiple signals to direct cellular responses that maintain homeostasis, the breakdown of which can lead to disease.
Regulation of neuronal fate by the JIP1 scaffold protein
Neuronal development and survival are controlled by a network of interacting signalling pathways. The JNK MAP kinase pathway has been strongly implicated in both processes. JNK pathway activity and localisation can be regulated by the JNK-interacting protein (JIP) family of scaffold proteins. JIP proteins also associate with other protein kinases, kinesin motor proteins, amyloid precursor protein, cell surface receptors and transcriptional regulatory proteins. These multiple interactions suggest that JIPs can integrate many signalling pathways. We have uncovered an important role for JIP1 in neuronal development. However, JIP1 also promotes JNK-mediated apoptosis and has been implicated in Alzheimer’s disease and stroke. We are investigating these dual roles of JIP1 with particular focus on how it integrates diverse signals and directs changes in neurone morphology and gene expression. We are also interested in the role of JIP1/JNK in nerve regeneration following injury. Our research provides novel insights into how signalling mechanisms direct neurone behaviour and will contribute to the design of appropriate therapies to combat brain injury and disease.