Supervisors: Simon Arthur, Ian Ganley, Dietmar Zaiss
Project Description:
Autophagy is a conserved process that allows cells to break-down and recycle proteins, organelles and remove intracellular pathogens. Although the basic mechanisms are conserved, it is now apparent that in mammalian cells autophagy is subject to complex regulation and can be divided into several distinct forms depending on the target structure. One area in which autophagy regulation is less well understood is in immune cell function. In particular, deregulation of autophagy can have severe consequences for immunological pathologies and, for example, lead to chronic inflammation. Lung diseases, such asthma and fibrosis are major clinical problems where the disease has been linked to elevated levels of Th2 type cytokines and inappropriate activation of innate immune cells. Increased autophagy flux has been reported in lung disease; however several questions remained unanswered. For example, what are the specific cell types involved and when is autophagy induced and how is it regulated? Importantly, it is unclear as to what extent autophagy might protect against or exacerbate disease pathology.
This project will use novel in vivo reporters for autophagy and mitophagy (a specialised form of autophagy that allows mitochondria to be broken down in the cell) to examine the timing and location of autophagy in models of asthma and lung fibrosis or following administration of IL-33, a cytokine strongly implicated in these processes. Once the location and timing of autophagy has been established in models of fibrosis, the autophagic cells will is isolated by FACS and proteomic analysis carried out to examine the changes occurring in these cells. Together these studies will shed light on how autophagy is regulated in lung disease and start to answer the question of if modulating autophagy levels is a valid target for future dug development in lung pathology.
The project will be a collaboration between labs in Dundee (Simon Arthur, Ian Ganley and David McEwan) and Edinburgh (Dietmar Zaiss) which together provide experience in immune signalling, autophagy and in vivo lung models.
References:
McWilliams TG, Prescott AR, Allen GF, Tamjar J, Munson MJ, Thomson C, Muqit MM, Ganley IG. (2016) mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J Cell Biol. 214(3):333-45.
McCarthy PC, Phair IR, Greger C, Pardali K, McGuire VA, Clark AR, Gaestel M, Arthur JSC (2198) 33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3. Immunol Cell Biol. In press, doi: 10.1111/imcb.12200
Arthur JS, Ley SC. (2013) Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 13(9):679-92.
To apply for this project, please go to this link.
