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
Regulation Of Perforin And Granzyme Expression In The Primary Cytolytic T Lymphocyte Response
Funder
National Health and Medical Research Council
Funding Amount
$756,000.00
Summary
The white blood cells known as cytolytic T lymphocytes (CTL) play important roles in elimination of some viruses, bacteria and tumours. Many vaccines and new therapies to prevent or control infections and cancer therefore seek to improve the production and activities of CTL. CTL kill infected cells and tumours by releasing packets of toxic molecules, including the pore-forming protein perforin and enzymes known as granzymes. However, while the roles of perforin and one granzyme, granzyme B, in c ....The white blood cells known as cytolytic T lymphocytes (CTL) play important roles in elimination of some viruses, bacteria and tumours. Many vaccines and new therapies to prevent or control infections and cancer therefore seek to improve the production and activities of CTL. CTL kill infected cells and tumours by releasing packets of toxic molecules, including the pore-forming protein perforin and enzymes known as granzymes. However, while the roles of perforin and one granzyme, granzyme B, in cell killing are now quite well understood, little is known about the other granzymes and how they contribute to immune protection. We have recently discovered that production of perforin and the three most prominent granzymes (A, B and C) can be separately controlled and that they are produced in different levels in different types of immune response. This suggests that they may each serve a different purpose and are therefore required in different amounts depending on the nature of the immune challenge. We have also found that an important hormone of the immune system, interleukin 4, has a profound effect on CTL, preventing their production of perforin and granzymes B and C and hence limiting their ability to kill target cells. In this project we plan a comprehensive analysis of perforin and granzyme production by CTL in response to different signals under controlled conditions in cell culture, and in response to different types of immune challenge in mice. We will also explore how interleukin 4 inhibits perforin and granzyme production and whether this has an impact on the effectiveness of the immune response. Mice in which one or more of the genes coding for perforin and granzymes has been damaged will be used to investigate how the absence of these molecules affects the immune response. We anticipate that these studies will suggest new strategies to improve therapeutic CTL induction by regulating perforin and granzyme production.Read moreRead less