Genevia: Development of novel bioinformatics algorithms to integrate multi-dimensional datasets for a systems biological view on ageing
i. Objective of research: To develop novel bioinformatics algorithms to integrate high-throughput data derived from animal models of ageing.
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: Our ESR will develop algorithms for a systems-biological view on ageing, thereby unravelling the complex molecular mechanisms associated with advanced age. We propose to generate in-depth, high-throughput proteome and ChIP-seq and RNA-seq profiles of several organs derived from naturally aged and progeroid mice as well as primary cells isolated from progeroid patients with inborn defects in DNA repair. This 3-dimensional information will be combined with physiological parameters and cellular data obtained from in vitro assays. The final goal is to delineate key pathways involved in lifespan regulation and to deliver protein biomarkers that may be used to monitor ageing, not only in mice, but also in humans. This holistic approach will facilitate the design of rationalized interventions to treat or prevent pathologies associated with advancing age.
iv. Originality and innovative aspects of the ESR project: The innovative integration of high-throughput genomics and proteomics data will provide a systems-biology view of ageing, thereby substantially increasing our fundamental knowledge on the ageing process. In combination with expected identification of accessible biomarkers, allowing monitoring of intervention studies, this will contribute to a better knowledge-driven drug development to prevent or counteract age-associated pathologies in order to improve quality of life to the elderly.
v. Integration of the ESR project to the overall research programme: Our ESR will work with the Serrano, Garinis, Lopez-Otin and Schumacher groups to get access to primary data from model organisms and patient cells as well with ProtATonce to combine our 3D datasets with derived ageing biomarkers in sera and cultured media.