Pregl award for excellent achievements was awarded to dr. Iva Hafner Bratkovič for her work on molecular mechanisms of neurodegenerative diseases, particularly on the mechanisms of prion protein conversion and the mechanisms of neuroinflammation in neurodegenerative diseases. Iva Hafner Bratkovič also engages into work with youth. She coordinated extremely successful project: Life sciences researchers:the next generation.
E.01 National awards
COBISS.SI-ID: 5843226Amyloid neurodegenerative diseases are also accompanied by neuroinflammation. One of the leading roles in this inflammatory process is played by IL-1β. Pro-IL-1β is processed by protein complexes called inflammasomes, which yield active IL-1β. NLRP3 inflammasomes are activated by Aβ aggregates (Halle et al., 2008) and prion protein fibrils (Hafner-Bratkovič et al., 2012) and NLRP3 or caspase-1 deficiency protects against disease progression in the mouse model of familial Alzheimer's disease (Heneka et al., 2013). Several cellular processes and a variety of different molecular triggers have been linked to NLRP3 inflammasome activation, but the molecular mechanism of the inflammasome assembly is unknown. Based on the structure of NLRC4 we prepared a molecular model of NLRP3, which guided the rational mutagenesis of NLRP3 in order to define the roles of NACHT and LRR domains in the response to soluble and particulate NLRP3 inflammasome activators. A number of truncated NLRP3 mutants were introduced into NLRP3-deficient macrophages and tested for their ability to respond to inflammasome instigators. The insight into the molecular mechanism of NLRP3 inflammasome activation is important for the design of specific NLRP3 inflammasome inhibitors for the development of novel therapies of chronic inflammatory diseases.
B.03 Paper at an international scientific conference
COBISS.SI-ID: 5792794NLRP3 inflammasome is a multiprotein complex which forms within cells in response to various triggers (ATP, microbial components, crystals, amyloid plaques etc.) The complex consists of a sensor protein NLRP3, adaptor protein ASC and procaspase-1, which self activates and converts cytokine pro-forms of IL1b and IL 18 into their mature forms. Despite increasing knowledge on the involvement of NLRP3 in a variety of pathologies, the mechanism of inflammasome activation is not understood and inhibitors targetting early steps of inflammasome assembly are lacking. Based on available structures of the proteins that comprise the inflammasome and on the models of NLRP3 we designed two groups of putative inhibitory peptides which were likely to disrupt the formation of the inflammasome. We showed that peptides inhibit the activation of caspase-1 and the release of IL-1β and IL-18 from myeloid cells in a concentration-dependent manner. Furthermore, we found that some of the peptides specifically inhibited the NLRP3 inflammasome and not other inflammasomes. Last year two students received Masters Degree including work described above. Additionally, the results were presented as a poster on FEBS3+ conference.
D.10 Educational activities
COBISS.SI-ID: 3942769