Die Rolle von Rho GRPasen und Zytoskelettdynamik bei der Erfassung und Phagozytose von Partikeln durch Makrophagen

Grunddaten zu diesem Projekt

Beschreibung

Phagocytosis, receptor-mediated engulfment of particles > 0.5 µm, is a specialist function restricted to professional phagocytes such as macrophages (from Greek, meaning "big eaters") and neutrophils. This function is critical for the clearance of pathogens, such as bacteria and fungi, as well as for the removal of debris and senescent cells. The basic scheme of phagocytic events is: surface ligands (pathogen-associated molecular patterns) on the particle --> phagocytic receptors --> signaling cascades --> Rho family GTPases --> actin cytoskeletal rearrangements --> particle engulfment and internalization. Our understanding of particle capture and engulfment by actin-mediated structures is patchy since it has been mainly derived from snapshots of these events or time-lapse imaging in two dimensions. However, actin dynamics can be imaged in 4D (3D time-lapse) using macrophages from Lifeact-EGFP mice, and the role of specific Rho GTPases and motor proteins in phagocytic events can be explored using available or near-ready conditonal knockout mouse models. The specific questions addressed in this project are: (1) what are the roles of the Rho GTPases Rac (Rac1 and Rac2), Cdc42, Rho (RhoA and RhoB) and RhoF in phagocytosis? (2) how is actin rearranged in space and time to detect, capture and engulf particles? and (3) what are the roles of the unconventional motor proteins myosin IXb (Myo9b) and myosin XVIIIa (Myo18a) in cytoskeletal dynamics and phagocytosis?