FORTH (G. Garinis group): Chronic inflammation and metabolic reprogramming during ageing
i. Objective of research: To dissect the functional relevance of impaired genome maintenance in chronic inflammation with advancing age.
ii. Current state of the art: To counteract DNA damage, mammalian cells employ genome maintenance pathways that are directed inwards to relentlessly scan and repair the genome. Instead, adaptive and innate immune mechanisms are often directed outwards to protect the self against pathogens. Recent work in our lab reveals that immune DNA-sensing mechanisms provide a direct link between innate immune signaling and the DNA damage response. At present, it remains unknown how cells sense damaged and foreign DNA, what is the functional role of DNA damage signaling in immune activation or what is the impact of the impact of persistent DNA lesions on chronic inflammatory diseases that gradually manifest with advancing age.
iii. Research methodology and approach: We will use a unique series of animals with engineered mutations in genes involved in Nucleotide Excision Repair (Ercc1-/-, Xpa-/-/Csb-/-) that show prominent signs of accelerated ageing and die prematurely. We will focus our studies on pancreas, the white adipose and liver derived from NER-defective animals to i. detect the gradual accumulation of single- and double-stranded DNA moieties in the cytoplasm, ii. dissect the functional relevance of accumulated DNA moieties in triggering proinflammatory circuits in progeroid and naturally aged animals, iii. Identify the protein complexes associated with DNA damage sensing and innate immune signaling and iv. delineate the in vivo relevance of DNA damage-driven inflammation in age-related metabolic reprogramming.
iv. Originality and innovative aspects of the ESR project: Until recently, DNA damage sensors as instigators of innate immune signaling received little attention due to the earlier views that as cellular DNA is compartmentalized within the nucleus, it would be ‘invisible’ to cytoplasmic and endosomal immune sensors. The novelty of our proposed line of research lies in the conceptual advance to mechanistically link the gradual accumulation of persistent DNA lesions with innate immune signaling and chronic inflammation during ageing.
v. Integration of the ESR project to the overall research programme: Our ESR will work with the Nollen group on neuroinflammatory diseases, with the Serrano group on senolytic drugs, with ProtATonce to analyze immune secretome and with Genevia on the analysis next-generation sequencing data (ChIP-seq, RNA-seq).