Cell Signalling Unit

Lab head: Professor Phil Robinson
Location: Cell Signalling Unit, Children's Medical Research Institute, 214 Hawkesbury Rd, Westmead

Website: http://www.cmri.org.au/CELL-SIGNALLING/default.aspx
Lab members: Professor Phil Robinson

Ring Stabilizer, compounds as potential novel tools to control pathogen clearance by phagocytes via the dynamin-actin interaction.

Primary supervisor: Phillip Robinson

Background: Dynamin is a mechano-chemical GTPase enzyme that plays crucial roles in diverse physiological processes fundamental to tissue health, such as endocytosis, phagocytosis, cytokinesis, cell migration and actin cytoskeleton assembly. To better understand multiple dynamin functions, our team has developed a diverse pharmacology around dynamin and have designed many classes of dynamin inhibitors that also block endocytosis in cells. Recently we obtained proof-of-concept for the use of such dynamin inhibitors as novel therapeutics for the treatment of human diseases such as epilepsy, cancer, or infectious disease.

Recent discoveries relevant to this project proposal: Phagocytosis is a unique form of endocytosis whereby cells such as macrophages engulf pathogenic bacteria to protect against infection. Although dynamin is required, its role in phagocytosis is not well understood. We have recently discovered novel dynamin modulating compounds that stimulate dynamin assembly into rings and increase dynamin GTPase activity. We have termed such compounds “Ring Stabilizers” (RS). In contrast to dynamin inhibitors, RS compounds do not block endocytosis, but promote actin polymerization and stress fibre formation in cells. RS compounds provide a new research tool alongside dynamin inhibitors that allow acute control for dynamin activity in cells.  Since dynamin and actin play crucial and orchestrated roles in the phagocytosis of pathogens, we have examined the effects of RS on bacterial phagocytosis. While dynamin inhibitors inhibited phagocytosis of bacteria, dynamin activators (i.e. RS compounds) promoted phagocytosis by macrophages in pilot studies.

Project proposal: Using RS compounds as novel tools, this project will test the hypothesis that dynamin activation promotes phagocytosis of pathogens. Two aspects will be examined: (i) Determination of effects of various RS compounds on phagocytosis of heat killed bacteria by macrophages. (ii) Deciphering the mechanisms by which RS promotes phagocytosis of bacteria. To answer these questions, an honours student will acquire skills in drug development, enzymology, biochemical assays, cell biology, fluorescence microscopy, and fluorescent activated cell sorter techniques.

Discipline: Pathology
Co-supervisors: Nick Gorgani