How does the innate immune system detect hallmarks of cell ageing?
Supervisors:
Leonie Unterholzner, Health and Medicine, Lancaster University
Rebecca Coll, Wellcome-Wolfson Institute For Experimental Medicine, Queen’s University Belfast
Richard Mort, Lancaster University
Summary:
Ageing is a complex process which affects all animals at the level of the whole organism, different tissues and cells. Even individual cells can age, and display hallmarks of ageing including persistent DNA damage, loss of telomere protection, damage of mitochondria and cell senescence. Recently, chronic inflammation has also been added to the list of ageing-associated features – also called “inflamm-aging”. In this project, we will investigate how DNA sensors of the innate immune system can detect cellular hallmarks of ageing to induce the chronic low-grade inflammation that is observed when we age. We will examine several key innate immune signaling pathways which have been implicated in the ageing process: the DNA sensors cGAS and IFI16 which activate the adaptor protein STING, and the NLRP3 inflammasome which activates caspase-1.
Each of these innate immune signaling cascades can have different downstream signaling outputs which then affect the cytokine profile within the tissue, and determine whether individual cells live, die or become senescent. In this project, we will culture human cells from young and aged donors, and assess the activation of innate immune signaling cascades using confocal microscopy, quantitative real-time PCR and ELISA. We will test whether aged cells show signs of DNA damage, mitochondrial damage or telomere attrition, and whether they possess higher levels of DNA in the cytosol which could activate the innate immune system. Cross-regulation of signaling pathways will be examined using small molecule inhibitors, CRISPR and RNA interference. Ultimately, this project will aim to map the molecular mechanisms that regulate innate immune homeostasis and its link to hallmarks of ageing in human cells.
The student will be part of two dynamic research laboratories at Lancaster University and Queen’s University Belfast, and will receive training in the handling of primary human cells, a large variety of cell and molecular biology techniques and associated analysis methods. This project would suit a student with a strong background in molecular and cell biology, and an interest in cell signaling and immunology.