Molecular mechanisms of thrombosis and immunothrombosis

In our laboratory we strive to understand the pathophysiological mechanisms that lead to thrombosis and immunothrombosis, an innate immune response that links coagulation to the recognition, containment and destruction of microbial pathogens.

Current research projects in the lab are:

Structural and single molecule studies of clotting and complement factors

Many biological processes such as blood coagulation and immune response depend on proteins with modular assembly. Resolving the spatial organization of the individual domains is key to understand their function. In our lab, structure-function relationships of proteins are investigated using biochemical, structural (X-ray crystallography, SAXS, NMR) and single molecule Förster resonance energy transfer (smFRET) techniques. Our goal is to observe, describe and predict the dynamic behavior of such modular assemblies thereby offering a mechanistic interpretation of their function. Our results will be used to explain disease-related clinical phenotypes associated with mutations or chemical modifications (i.e. oxidation, phosphorylation, etc.) of the native proteins as well as to design effective strategies to diminish or enhance their function on demand.

This workflow has been successfully applied to solve, for the first time, the structural architecture of prothrombin in solution and will be further implemented to understand how macromolecular complexes assembled on phospholipid bilayers work at the molecular level.

Pozzi N. et al., PNAS 2014, Pozzi N. et al., JBC 2016, Pozzi N. et al., JBC 2016

Structural and mechanistic studies on antigen-antibody recognition in autoimmune disorders

Autoimmune disorders are characterized by the presence of circulating antibodies (autoantibodies) that mistakenly recognize self proteins (antigens). By investigating the nature of the autoantibodies, the goal of this project is to discover and classify new families of antigens, elucidate how antigen-antibody recognition occurs at the molecular level and how such interaction may disrupt hemostasis. In this context, the Antiphosholipid Syndrome (APS) is of particular relevance. APS is the most common acquired thrombophilia (= tendency to spontaneously form blood clots). Clinically APS is characterized by venous and arterial thrombosis as well as pregnancy morbidity. One of the most serious complications of APS occurs when a clot forms in the brain and causes a stroke. 30% of strokes in individuals younger than age 50 are due to APS. Other neurological symptoms include chronic headaches, dementia (similar to the dementia of Alzheimer’s disease), and seizures. APS is challenging to diagnose, it has no specific cure and has uncertain etiology. Our lab is currently investigating the structure-function relationships of the two major protein antigens recognized by the antiphospholipid antibodies, i.e. prothrombin and beta-2 glycoprotein-I.

Acquasaliente L, Biochem J. 2016; Pozzi N, J Thromb Haemost. 2013; Pozzi N, Protein Sci. 2010