In vivo analysis of the role of autophagy in the lung

Supervisors: Simon Arthur, 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. Phosphoprotein screens on IL-33 pathways, a cytokine linked to asthma and fibrosis, have identified several proteins involved in autophagy regulation as targets of IL-33 signalling.  Once the location and timing of autophagy has been established in models of fibrosis, small molecule inhibitors and/or knockout animals will be used to determine the role of specific pathways in autophagic regulation in lung pathology. 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 disease.

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

  1. 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.
  2. McEwan DG, Popovic D, Gubas A, Terawaki S, Suzuki H, Stadel D, Coxon FP, Miranda de Stegmann D, Bhogaraju S, Maddi K, Kirchof A, Gatti E, Helfrich MH,Wakatsuki S, Behrends C, Pierre P, Dikic I. PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. (2015) Mol Cell. 57(1):39-54. 13(9):679-92.
  3. Arthur JS, Ley SC. (2013) Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 13(9):679-92.
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