The IGSAD seeks understanding of the fundamental processes that cause ageing and ageing-associated diseases. DNA repair deficiencies lead to developmental abnormalities, cancer predisposition, and premature ageing in human patients. DNA damage thus causally contributes to cancer, functional decline, and ageing. The past decades of DNA repair research has brought to light sophisticated repair machineries and networks of DNA damage response pathways. The exorable complexity of pathologies caused by DNA damage in human, however, requires an organismal understanding of the responses and physiological adaptations to genome instability. Using mouse models of premature ageing, we have uncovered intriguing links between persistent DNA lesions and the regulation of longevity assurance pathways that give us a more complete understanding of how ageing organisms respond to the accumulation of DNA damage.
We are primarily employing the nematode worm C. elegans to understand how developing as well as ageing multicellular organisms respond to DNA damage. In the nematode we have uncovered the germline DNA damage induced systemic stress resistance (GDISR) that is mediated by the ancestral innate immune system. GDISR becomes established in somatic tissues through activation of the ubiquitin proteasome system. We are interested in exploring mechanisms and consequences of DNA damage-induced immune responses in nematodes and mammals.
We are integrating transcriptome analysis, genetics, and biochemical approaches to gain a systems understanding of organismal DNA damage responses. Particularly, the powerful genetics of C. elegans allow us to identify new genes that are important for maintaining genome stability both in proliferative and postmitotic cell types. Based on findings in C. elegans, we are using DNA repair deficient mice to translate our findings into mammalian disease models. We are thus pursuing a more complete understanding of organismal DNA damage responses that we believe will impact the development of future intervention strategies aimed at preventing aging-associated diseases by extending healthspan and might benefit patients that suffer from rare congenital syndromes caused by defects in genome maintenance systems.