Targeting mechanisms of Thrombo-inflammation

Introduction

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 the outcome of viral or bacterial infection, cardiovascular disease, cancer, and other diseases.

Unmet Medical Need

The lack of mechanistic insights has 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.

Mechanism of Action

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 conceptual framework for thrombo-inflammatory diseases.

Research Objectives

To enable future translation of this novel mechanism, I aim to address the following open questions:

1. How is this molecular switch regulated in an organ and context-specific fashion (in vitro work; cell-specific inducible TF±IFNAR1 deficient mice)?
2. What are the consequences of this molecular switch for intracellular signaling, inflammation, and mitochondrial metabolism (omics with bioinformatic analyses)?
3. What are the molecular structures required for the TF-IFNAR1 interaction (cross-linking, crystallography, phage display, computational modeling)?

Expected Outcomes

I expect that answering these questions will lead to new diagnostic and therapeutic approaches revolutionizing the way we detect and treat thrombo-inflammatory diseases.