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IS-AUR-Samarb.progr. Norge Frankrike

Role of PARP3 in normal continuos and stress-induced neurogenesis in brain.

Tildelt: kr 50 000

Poly(ADP-ribosyl)ation is a post-translational modification of proteins mediated by Poly(ADP-ribose) polymerases (PARPs). PARPs catalyse the transfer and polymerisation of ADP-ribose units from NAD+ to form a ramified polymer, the poly(ADP-ribose) (PAR), covalently linked to acceptor proteins or PARP themselves. DNA strand breakage was long considered as the major trigger of PAR synthesis through the activation of PARP1. Preliminary results in the French lab reveal enhanced expression of PARP3 in response to oxidative stress and an increased sensitivity of PARP3-/- mouse embryonic fibroblats to oxidative damage, thereby suggesting that PARP3 responds to oxidative DNA base lesions. Of note, ROS are implicated in several physiological settings. Among them, ROS play important roles in cell signaling and homeostasis during neurogenesis and in hippocampal synaptic plasticity. Furthermore, oxidative stress is a hallmark of stress-induced brain injury. Together, these observations prompt us to investigate a poss ible role of PARP3 in ROS protection and neurogenesis in brain. In support of this hypothesis using zebrafish as a model system, a recent study revealed critical functions of PARP3 in vertebrate neural development. Chromatin associated PARP3 predominantly localizes around developmental genes involved in neurogenesis and its reduced expression in zebrafish leads to severe developmental defects caused by inappropriate ectodermal and neural crest differentiation. Based on these data, the scientific objectiv e of the current project is to investigate a possible function of PARP3 in induced and continuous neurogenesis in brain. The French partner has engineered a mouse model deficient in PARP-3 and developped biochemical and cellular tools (purified protein, a ntibodies, depleted cell lines etc) to reach this objective. The Norwegian partner has key expertise and a track record in the in-depth study of continuos and stress-induced neurogenesis.


IS-AUR-Samarb.progr. Norge Frankrike