Investigating the link between oxidative stress and endosomal sorting in disease
Correct sorting of cargo proteins in the endosomal-lysosomal system is required for normal cellular function. Defects in endosomal sorting are associated with numerous metabolic disorders such as insulin resistance and also with neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Oxidative stress is also recognized as a contributing factor to the aforementioned disorders. The aim of this project will be to investigate the mechanistic link between oxidative stress and endosomal-lysosomal sorting. We have recently obtained evidence showing that specific components of endosomal sorting machineries are depleted from fat cells (adipocytes) upon exposure to oxidative stress and that this results in reduced glucose uptake in response to insulin. The reduced glucose uptake is likely to result from the glucose transporter GLUT4 not being sorted efficiently to an insulin sensitive compartment when endosomal machinery is perturbed (1). We propose that oxidative stress similarly affects the same endosomal sorting machinery in other cell types such as neurons but will impact on different cargoes resulting in cell type specific defects.
The project will explore the signaling pathways by which oxidative stress leads to depletion of endosomal sorting proteins in cell types relevant to metabolic disorders and neurodegeneration. The student will use a variety of cell biology, molecular biology and biochemistry techniques in the project.
The findings of the study are likely to provide mechanistic insight into shared molecular mechanisms of prevalent diseases and inform future therapeutic strategies to combat these diseases.
We welcome all-year around applications from applicants able to self-fund and those looking to apply for external funding.
(1) Koumanov, F., Pereira, V. J., Whitley, P. and Holman, G. D. (2012) GLUT4 traffic through an ESCRT-III-dependent sorting compartment in adipocytes. PLoS One. 7(9): e44141
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FTE Category A staff submitted: 24.50
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