Aging is the greatest risk factor for the majority of chronic diseases, including muscle wasting, autoimmunity, Alzheimer’s and cardiovascular disease (CVD). The UK’s population of over-65-year-olds will increase by 8.6 million in 50 years, with the NHS spending twice as much on 65-year-olds and five times as much on 85-year olds than the younger adult population. These costs are unsustainable if we do not identify ways to ensure a longer health-span in the aging population.
Ageing and age-related diseases share basic mechanistic pillars that fundamentally converge on sterile, low-grade inflammation, called Inflamm-aging. This is the result of chronic stimulation of the innate immune system, particularly macrophages. Aging is characterized at the cellular level by a progressive accumulation of dysfunctional proteins and damaged organelles leading to progressive degeneration and organ damage1.
Autophagy, an evolutionarily conserved cellular housekeeping pathway, removes damaged cellular organelles preventing premature and dangerous cell death. It plays a major role in maintaining cellular homeostasis and influencing both life- and health-span. Defective autophagy leads to premature aging in numerous model species, whilst enhanced autophagy promotes longevity2. The autophagy pathway is composed of a number of autophagy related proteins (ATG). One of these, ATG5, can also modulate both the immune system and the cellular death (apoptosis) pathways. Autophagic function declines with age, but whether this leads to Inflamm-aging is unclear.
We hypothesise that ATG5 exerts a central role in Inflamm-aging, by limiting the exposure of the innate immune system to inflammatory self-proteins3.
Our preliminary data confirms that mammalian cells lacking expression of ATG5 fail to form apoptotic bodies and undergo secondary necrosis releasing inflammatory nuclear material. In addition, lymphocytes of patients with the autoimmune disease systemic lupus erythematosus (SLE), express significantly less ATG5. Following cellular stress SLE-lymphocytes undergo premature death that activates macropahges to secrete pro-inflammatory cytokines including TNF and type I interferons in a STING dependent manner. Whilst SLE tends to affect younger women, they have a greatly exacerbated risk of developing severe CVD and cognitive decline, both seen predominantly in the aged population.
In this project we will ask two fundamental but related biological questions:
1) How does ATG5 control apoptotic body formation, so ensuring the safe disposal of cellular nuclear debris?
2) How does the loss of ATG5 in stressed and dying cells activate the STING pathway of bystander innate immune cells?
Data generated from this thesis will provide the mechanistic link between declining autophagy and inflammation and open up new avenues to reducing the consequences of Inflamm-aging.
To address these questions, the successful applicant will master a number of cell biological techniques including confocal microscopy to analyse the morphology of apoptotic cells, cell transfection to rescue cells deficient in ATG5, Western blotting to analyse the level of cellular proteins, and ELISAs to assay for pro-inflammatory cytokines. In addition, whole cell transcriptomic changes (assessed by RNAseq and verified by quantitative PCR) along with metabolic changes (assessed by Sea-horse and mass spectrometry) resulting from loss of ATG5 in lymphocytes and their effect on macrophage function will be undertaken.
For instructions on how to apply for an EASTBIO PhD studentship please refer to http://www.eastscotbiodtp.ac.uk/how-apply-0
Contact Dr Mohini Gray [email protected]
before you apply.
We anticipate that our first set of interviews will be in the week commencing 10th February 2020 with awards made the following week.
Please submit all required documents directly to [email protected]
The research group is located in the University of Edinburgh Centre for Inflammation Research; a world-class research environment at the interface between biological and medical science, with multidisciplinary groupings focused on inflammation, infection, disease and repair. The Centre is based within the Edinburgh Medical School in the outstanding facilities of the Queen’s Medical Research Institute at the site of the Royal Infirmary of Edinburgh hospital, maximising future translational opportunities.
1 Madeo, F., Zimmermann, A., Maiuri, M. C. & Kroemer, G. Essential role for autophagy in life span extension. J Clin Invest 125, 85-93, doi:10.1172/JCI73946 (2015).
2 Pyo, J. O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun 4, 2300, doi:10.1038/ncomms3300 (2013).
3 Franceschi, C., Garagnani, P., Vitale, G., Capri, M. & Salvioli, S. Inflammaging and 'Garb-aging'. Trends Endocrinol Metab 28, 199-212, doi:10.1016/j.tem.2016.09.005 (2017).