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Projects / Programmes source: ARIS

The functional role of cell death in different NLRP3 inflammasome activation pathways and its application for innovative cancer immunotherapy

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Research activity

Code Science Field Subfield
3.01.00  Medical sciences  Microbiology and immunology   

Code Science Field
B001  Biomedical sciences  General biomedical sciences 

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
Keywords
inflammasome, gasdermin D, pore formation, cytokine release
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (13)
no. Code Name and surname Research area Role Period No. of publications
1.  14360  PhD Mojca Benčina  Biotechnology  Researcher  2019 - 2022  392 
2.  55265  Elvira Boršić  Biochemistry and molecular biology  Junior researcher  2021 - 2022  11 
3.  54624  Tea Govednik  Pharmacy  Technical associate  2020  9 
4.  23563  PhD Iva Hafner Bratkovič  Neurobiology  Head  2019 - 2022  211 
5.  06628  PhD Roman Jerala  Biochemistry and molecular biology  Researcher  2019 - 2022  1,190 
6.  36853  PhD Lucija Kadunc Polajnar  Neurobiology  Junior researcher  2019 - 2020  43 
7.  53665  Špela Malenšek  Biochemistry and molecular biology  Researcher  2020 - 2022  17 
8.  21426  PhD Mateja Manček Keber  Pharmacy  Researcher  2019 - 2022  159 
9.  53734  Peter Pečan  Biochemistry and molecular biology  Researcher  2020 - 2022  17 
10.  38275  Anja Perčič    Technical associate  2019 - 2022  0 
11.  50616  Arne Praznik  Biochemistry and molecular biology  Researcher  2019 - 2022  35 
12.  54582  Tadej Satler  Biotechnology  Technical associate  2020  10 
13.  37644  PhD Petra Sušjan Leite  Biotechnology  Junior researcher  2019 - 2020  49 
Organisations (1)
no. Code Research organisation City Registration number No. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,007 
Abstract
Scientific background and problem identification. Inflammasomes are multiprotein complexes that serve as platforms for activation of inflammatory caspases. NLRP3 is a cytosolic innate immune sensor that upon activation forms an inflammasome. Recently we identified the minimal size of NLRP3, needed for inflammasome activation (Hafner-Bratkovič et al., Nature Communications, 2018). The activation of NLRP3 inflammasome is specifically intriguing as it can lead to various outcomes. In canonical and noncanonical inflammasome activation, the secretion of mature IL-1β is coupled to cell death, while alternative inflammasome activation is characterized by IL-1β secretion from the living cells. Gasdermin D, which upon cleavage by inflammatory caspases makes pores in the membrane, seems to be required for both, IL-1β release from dead and living cells, yet how the cell fate is decided, remains unknown. Objectives of the study. Within this project we plan to: 1. to investigate the mechanisms underlying inflammasome activation and gasdermin D pore formation. We plan to investigate kinetics of gasdermin D cleavage and define inflammasome composition and inflammasome localization upon activation of various inflammasome pathways. Mutagenesis of gasdermin D variants will provide the insight into gasdermin D pore formation and gasdermin D variants with different pore-forming capabilities will be used in further applications. 2. to develop cells which release bioactive molecules on demand. We plan to use properly controlled formation of gasdermin D pores for release of selected molecules from living cells or dying cells. Recently developed fast logic systems based on split proteases such as tobacco etch virus (TEV) protease (Fink et al., Nature Chemical Biology, 2019) will provide additional level of regulation of  gasdermin D cleavage and pore formation. 3. to analyze the potential of the pyroptotic cell death for antitumor immunity. In this project we propose to use designed pyroptosis and induced cytokine release in non-macrophage cells for cancer immunotherapy. Relevance and potential impact of the results. The project combines investigation of an important fundamental mechanism with potential therapeutic application and includes innovative combination of our expertise in innate immunity (molecular mechanisms of NLRP3 inflammasome activation) and synthetic immunology (logic in mammalian cells) to first determine the differences in the mechanisms of pyroptotic cell death and apply this knowledge to either provide the prolonged proinflammatory cytokine release or to engage rapid immunostimulatory cell death. In this project we envisage that the inhibition of pyroptosis and sustained release of IL-1β should prove beneficial in vaccine development, while induction of tumor cell pyroptosis could open a novel realistically applicable strategy for cancer immunotherapy.
Significance for science
In the past decade inflammasomes, particularly NLRP3 inflammasome, has gained a lot of attention due to its connection to a variety of pathological conditions.  Studies describing the mechanisms of NLRP3 activation and gasdermin family pore formation and connection to pyroptosis have be published in top science journals such as Nature, Science, Nature Immunology and Immunity.   Those studies established the link between gasdermin D and IL-1ß release from living and dead cells, however, the mechanisms how this in fact happens are ill-defined. The key contributions of our research will be: 1)   in providing the mechanistic insight into NLRP3 inflammasome activation pathways and gasdermind D pore formation, 2) the exploitation of gained knowledge for the usage of gasdermin D pores as means for release of biologically active molecules and  cancer immunotherapy.   Within this project we combine the expertise from molecular biological mechanisms of signaling complexes to synthetic immunology to provide the insight into molecular mechanisms of processes that lead to gasdermin D pore formation and its utilization for release of cytokines and induction of tumor cell death. Our approach represents innovative contribution in these very competitive disciplines and might open new therapeutic possibilities for cancer immunotherapy. The members of the research group will pass their knowledge to scientific community through international workshops and conferences and publication of scientific papers in peer-reviewed journals.
Significance for the country
In the past decade inflammasomes, particularly NLRP3 inflammasome, has gained a lot of attention due to its connection to a variety of pathological conditions.  Studies describing the mechanisms of NLRP3 activation and gasdermin family pore formation and connection to pyroptosis have be published in top science journals such as Nature, Science, Nature Immunology and Immunity.   Those studies established the link between gasdermin D and IL-1ß release from living and dead cells, however, the mechanisms how this in fact happens are ill-defined. The key contributions of our research will be: 1)   in providing the mechanistic insight into NLRP3 inflammasome activation pathways and gasdermind D pore formation, 2) the exploitation of gained knowledge for the usage of gasdermin D pores as means for release of biologically active molecules and  cancer immunotherapy.   Within this project we combine the expertise from molecular biological mechanisms of signaling complexes to synthetic immunology to provide the insight into molecular mechanisms of processes that lead to gasdermin D pore formation and its utilization for release of cytokines and induction of tumor cell death. Our approach represents innovative contribution in these very competitive disciplines and might open new therapeutic possibilities for cancer immunotherapy. The members of the research group will pass their knowledge to scientific community through international workshops and conferences and publication of scientific papers in peer-reviewed journals.
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