Investigating Nuclear Pore Complex Structure Prior to Nuclear Rupture in NETosis

Neutrophils are innate immune cells crucial for host defense against pathogens. Patients with a low number of neutrophils have recurrent infections which they fail to clear. Neutrophils eliminate invaders using various strategies including the release of neutrophil extracellular traps (NETs) during NETosis. NETs are weblike DNA structures coated with antimicrobial and cytotoxic proteins which trap and neutralize pathogens. However, NETosis can also damage surrounding tissues and propagate inflammation thereby worsening the outcome of chronic inflammatory diseases including cancer and diabetes. Therefore, controlling when and where neutrophils NETose would allow us to stop the propagation of infection and alleviate the burden of chronic inflammation. To this end, our lab aims to identify the mechanisms driving NETosis. A critical and not understood step in NETosis is the remodeling and rupture of the nuclear membrane, required for the DNA to exit the nucleus. My project will investigate how the nuclear membrane is remodeled with a focus on the nuclear pore complex (NPC) – a large transmembrane channel that spans the two nuclear membranes. We will use a combination of quantitative live cell imaging, super resolution microscopy and genetics to test the hypothesis that NPCs are weak points from where the nucleus rupture during NETosis.