Summary
The recent Covid-19 pandemic dramatically illustrated (i) the clinical relevance of thrombo-inflammation (the interplay of coagulation and inflammation) and (ii) our limited understanding of molecular mechanisms of thrombo-inflammation. Thrombo-inflammation is a frequent disease-driving mechanism, impairing out-come of viral or bacterial infection, cardiovascular disease, cancer and other diseases. The lack of mechanistic insights hampered the development of specific therapies. My group recently discovered a new molecular link between coagulation and inflammation that addresses this enormous unmet medical need: the initiator of coagulation, tissue factor (TF, F3, CD142), forms a previously unknown heterodimer with the cytokine receptor IFNAR1 (Interferon-alpha/beta receptor alpha chain) on resting cells. In this heterodimer, TF and IFNAR1 are both inactive. Upon stimulation (e.g. fVII/fVIIa, LPS, polyIC) the heterodimer dissociates, activating TF-mediated coagulation, IFNAR1-mediated inflammation, and cellular metabolism. This provides a novel, yet simple molecular switch simultaneously controlling coagulation, inflammation, and metabolism. This “switch” is expected to provide a new conceptional framework for thrombo-inflammatory diseases. To enable future translation of this novel mechanism, I aim to address the following open questions (i) how is this molecular switch regulated in an organ and context specific fashion (in vitro work; cell-specific inducible TF±IFNAR1 deficient mice)? (ii) what are the consequences of this molecular switch for intracellular signaling, inflammation, mitochondrial metabolism (omics with bioinformatic analyses)? and (iii) what are the molecular structures required for the TF-IFNAR1 interaction (cross-linking, crystallography, phage display, computational modeling)? I expect that answering these questions will lead to new diagnostic and therapeutic approaches revolutionizing the way we detect and treat thrombo-inflammatory diseases.
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| Web resources: | https://cordis.europa.eu/project/id/101141561 |
| Start date: | 01-11-2024 |
| End date: | 31-10-2029 |
| Total budget - Public funding: | 2 499 000,00 Euro - 2 499 000,00 Euro |
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Original description
The recent Covid-19 pandemic dramatically illustrated (i) the clinical relevance of thrombo-inflammation (the interplay of coagulation and inflammation) and (ii) our limited understanding of molecular mechanisms of thrombo-inflammation. Thrombo-inflammation is a frequent disease-driving mechanism, impairing out-come of viral or bacterial infection, cardiovascular disease, cancer and other diseases. The lack of mechanistic insights hampered the development of specific therapies. My group recently discovered a new molecular link between coagulation and inflammation that addresses this enormous unmet medical need: the initiator of coagulation, tissue factor (TF, F3, CD142), forms a previously unknown heterodimer with the cytokine receptor IFNAR1 (Interferon-alpha/beta receptor alpha chain) on resting cells. In this heterodimer, TF and IFNAR1 are both inactive. Upon stimulation (e.g. fVII/fVIIa, LPS, polyIC) the heterodimer dissociates, activating TF-mediated coagulation, IFNAR1-mediated inflammation, and cellular metabolism. This provides a novel, yet simple molecular switch simultaneously controlling coagulation, inflammation, and metabolism. This “switch” is expected to provide a new conceptional framework for thrombo-inflammatory diseases. To enable future translation of this novel mechanism, I aim to address the following open questions (i) how is this molecular switch regulated in an organ and context specific fashion (in vitro work; cell-specific inducible TF±IFNAR1 deficient mice)? (ii) what are the consequences of this molecular switch for intracellular signaling, inflammation, mitochondrial metabolism (omics with bioinformatic analyses)? and (iii) what are the molecular structures required for the TF-IFNAR1 interaction (cross-linking, crystallography, phage display, computational modeling)? I expect that answering these questions will lead to new diagnostic and therapeutic approaches revolutionizing the way we detect and treat thrombo-inflammatory diseases.Status
SIGNEDCall topic
ERC-2023-ADGUpdate Date
21-11-2024
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