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Identifier 000448838
Title Deciphering the functional link between DNA damage and the innate immune response in macrophages and pancreas
Alternative Title Διερεύνηση του μοριακού μηχανισμού που συσχετίζει την πρόκληση γενετικών αλλοιώσεωνμε την εκδήλωση ανοσολογικών αποκρίσεων στα μακροφάγα και το πάγκρεας
Author Χατζηδουκάκη, Ουρανία
Thesis advisor Ζαφειρόπουλος, Αλέξανδρος
Γαρίνης, Γεώργιος
Reviewer Τσατσάνης, Χρήστος
Αθανασάκη, Ειρήνη
Σουρβίνος, Γεώργιος
Χαμηλός, Γεώργιος
Νότας, Γεώργιος
Abstract The functional link between DNA damage, chronic inflammation, tissue degeneration and aging still remains elusive. Using a well-established, progeroid mouse model, which carries an ERCC1-XPF DNA repair defect, we show that persistent DNA damage leads to loss of tissue architecture and fibrosis in Ercc1-/- pancreata. We find that DNA damage-driven R-loops causally contribute to the release and build-up of single-stranded (ss)DNAs in the cytoplasm of cells triggering a viral-like immune response in Ercc1-/- and naturally aged pancreata. To alleviate the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or RNase H nucleases in inflamed Ercc1-/- pancreatic cells. Importantly, treatment of Ercc1-/- animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs ameliorating the proinflammatory response. Thus, DNA damage-driven ssDNA moieties causally contribute to tissue degeneration with advancing age paving the way for novel rationalized intervention strategies against age-related chronic inflammation.
Language English, Greek
Subject Aging
Issue date 2022-07-29
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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