Nicola Pozzi, Ph.D. » Investigators

Cardiovascular Research Interests:

Primary area of research:

• Thrombosis and hemostasis
• Drug development

Related area of research:

• Molecular mechanisms of thrombus formation
• Structure and function of clotting and complement factors
• Acquired and Inherited thrombophilia
• Development of biotherapeutics via protein engineering

Summary of cardiovascular research:

Hemostasis is the process that causes bleeding to stop. Inherited genetic and acquired disorders perturbing hemostasis often lead to excess bleeding (hemorrhage) or clotting (thrombosis). For example, hemophilic patients carrying defects in clotting factors VIII (hemophilia A) or IX (hemophilia B) frequently bleed in their muscle and joints. In contrast, patients suffering from FV Leiden, Protein C deficiency, ATIII resistance, VWF disease, Antiphospholipid Syndrome, sepsis, and cancer manifest venous and arterial thrombosis leading to pulmonary embolisms, myocardial infarction, stroke, and organ failure.

Our research focuses on two lines of investigation:

1) Molecular Mechanisms of Thrombus Formation. Coagulation is a cascade of enzymatic reactions leading to the formation of a fibrin clot. We investigate how plasma proteins and clotting factors interplay at the molecular level, how they sense the surrounding microenvironment, and how their catalytic machinery works. To achieve our goals, we apply a unique combination of protein engineering, enzymology, structural biology, and single molecule spectroscopy.

For instance, we recently discovered that coagulation factor II (FII) or prothrombin circulates in two forms at equilibrium, “closed” and “open,” brokered by the flexibility of the linker regions, identified strategies to stabilize its alternative conformations, and solved the first X-ray crystal structure of the closed form. Building upon these new findings, we are now investigating the role of such equilibrium in healthy conditions and disease states, such as Antiphospholipid Syndrome. We are also interested in understanding the physiological role of the plasma protein b₂-glycoprotein I (b₂GPI) and elucidating the catalytic cycle of the thiol-isomerase protein disulfide isomerase (PDI), whose presence in the circulation causes thrombus formation.

2) Development of Biotherapeutics via Protein Engineering. About 10% of Americans aged 75 and older and 6% of Americans between the ages of 65 and 74 use blood thinners. Yet, all current medications suffer from side effects thus affecting patients’ safety and lifestyle. Alternative and more effective ways to manage blood clotting are needed.

To fill this unmet clinical need, we are developing a new family of biotherapeutics through protein engineering with novel mechanisms of action that potentiate the protein C pathway and inhibit prothrombin activation.