Under this fellowship the applicant will study a n important group of enzymes and molecular delivery machines involved in clotting disease, immune dysfunction and cancer.
Understanding How Perforin Forms Pores: The Role Of Calcium And Lipids.
Funder
National Health and Medical Research Council
Funding Amount
$797,813.00
Summary
This grant aims to study perforin, a key part of the mammalian immune system. The work will facilitate the development of perforin inhibitors. It is anticipated that these data will be of utility in developing first in class drugs to improve the success of bone marrow transplantation.
Cytotoxic T Lymphocyte Synapse Formation And Serial Killing: When Breaking Up Is Hard To Do.
Funder
National Health and Medical Research Council
Funding Amount
$626,688.00
Summary
Killer T cells are a specialised group of immune cells, which destroy cancerous and infected cells. When killer T cells find a target, they attach and secrete toxic molecules. It then detaches from the dying target, so that it may go on to kill other cells. If it doesn’t detach properly, it remains bound to the target cell and results in an improper immune response. This proposal will investigate how the killer cell detaches, which is essential for an efficient immune response.
Structural Studies On The Immune Effector Perforin: Developing Mechanism-based Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$1,116,594.00
Summary
Perforin is an essential weapon deployed by the human immune cells in order to destroy virally infected or cancerous cells. Despite this key role, unwanted or excessive perforin function can result in disease and can severely impact on successful treatment of leukaemia through bone marrow transplantation. This application aims to understand the molecular details of perforin function, and to apply this knowledge to develop perforin inhibitors.
Analysis Of The Molecular Functions Of Perforin: A Critical Role In Tumor Immunosurveillance
Funder
National Health and Medical Research Council
Funding Amount
$318,916.00
Summary
Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer ....Over the past decade, great steps have been made in defining the key molecules used by killer cells of the immune system that eliminate cancerous- and virus-infected cells and many of these advances have originated in our laboratory. It is now clear that granule-mediated cytolysis is a key mechanism for controlling both primary and metastatic cancers in transplanted syngeneic, allogeneic and xenogeneic tumor models in mice. The pore-forming protein, perforin is indispensable for effective killer cell function in these models. But the role for perforin expressing killer cells in tumor surveillance against spontaneous tumorigenesis is still hotly debated. Our proposal to study tumor development in perforin-deficient p53-mutant tumor prone mice will enable us to answer this question. Furthermore, the molecular mechanisms by which perforin functions are poorly understood. We therefore also propose to complete a structure-function analysis of perforin using unique tools and information that our laboratory has at its disposal. The long-term goal will be to better understand the function of perforin at the molecular level such that the rationale design of therapeutic perforin inhibitors may become a reality for future regulation of killer cell effector functions in disease.Read moreRead less