The Molecular And Cellular Trajectories Of Clonal Dendritic Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$826,742.00
Summary
Dendritic cells (DCs) are a blood cell type with a crucial role in our immune system. They are made in the bone marrow from stem and progenitor cells. How each of these cells individually makes DCs is complex and dynamic. We seek to understand this using cutting edge technologies to track each cell’s step-by-step role in this important process. This knowledge may help the use of DCs in the treatment of several diseases including autoimmunity and cancer.
The Role Of C-Cbl In The Regulation Of T Cell Signalling And Development
Funder
National Health and Medical Research Council
Funding Amount
$527,250.00
Summary
c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) ....c-Cbl is a member of a multi-adaptor protein family that can interact with many signalling proteins via its different domains. Cbl proteins have been implicated as negative regulators of signalling pathways involving protein tyrosine kinases (PTKs). PTKs are enzymes which add phosphate groups to tyrosine residues on other protein substrates, and the process of tyrosine phosphorylation acts as a potent biochemical switch to turn signalling cascades on and off. Studies of Cbl-deficient (knockout) mice show that Cbl proteins are important in regulating the development of, and signalling by, cells of the immune system called T cells. c-Cbl knockout mice show greatly enhanced PTK-signalling responses and deregulated activity of a PTK called ZAP-70. The mechanism of this is not known, but analysis of a c-Cbl mutant mouse shows that this is not dependent on the tyrosine kinase binding (TKB) domain of c-Cbl. Therefore other functional domains of Cbl must be responsible for the increased signalling response in the c-Cbl knockout mouse. One candidate is the highly conserved RING finger domain which can modify Cbl-associated PTKs by addition of ubiquitin molecules. Ubiquitination of a protein often, but not always, leads to its degradation, and this could be how Cbl controls the strength and duration of signalling in T cells. However there may be other functions of the conserved RING finger yet to be identified. c-Cbl itself is prominently and very rapidly modified by tyrosine phosphorylation on tyrosine 737 by the Fyn PTK following T cell activation, but the role of this modification is not known and could also be essential for c-Cbl s function in T cells. We plan to investigate the roles of the RING finger domain and Fyn-mediated tyrosine phosphorylation in c-Cbl regulation of T cell signalling by analyzing knock-in mice that carry specific mutations disrupting the RING finger or tyrosine 737 in the c-Cbl gene.Read moreRead less
The human immune system comprises many different types of cells that can detect foreign molecules. My research will lead the way to understanding some of the most abundant, yet least well understood, cells within this system, collectively known as 'unconventional T cells'. This knowledge is essential to optimally and efficiently manipulate the immune system in health and disease.
Following The T Cell Repertoire Over The Human Life Course
Funder
National Health and Medical Research Council
Funding Amount
$473,159.00
Summary
T cells are critical to human health being our second and last line against infectious disease and cancer. However, we know very little about how this important immune compartment operates on a top-down scale. This project will use new technology to resolve this immune compartment to high detail. We will then use this new method to track the T cell compartment from the first years of life and across years of adult life to see how this vital immune compartment evolves along the human life course.
Asymmetric Cell Divison In T Cell Development: Consequences For Immunity And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$642,608.00
Summary
Human health depends upon the development of an immune system that can effectively control infection without damaging normal tissue. In this project, we assess a new paradigm by which immune cell development might be controlled, in which an immune cell precursor divides in such a way that its two daughters inherit different molecular constitutents that subsequently regulate the adoption of different cell fate. The likely consequences of this phenomonon on immunity and cancer will be explored.
Role Of The CD8-Heparan Sulfate Interaction In CD8+ T Cell Development And Function
Funder
National Health and Medical Research Council
Funding Amount
$649,135.00
Summary
The immune system can recognise a large array of foreign pathogens without reacting to self-components. For this to occur T cells, the main mediators of immunity, must be made to tolerate self-molecules as they develop in the thymus. We have identified a novel interaction between a molecule called CD8 on T cells and a complex carbohydrate called heparan-sulfate, which helps auto-reactive T cells to be eliminates in the thymus. The aim of this project is to further investigate this phenomenon.
The Mechanisms Of Epithelial Cell Survival That Govern Thymus Function
Funder
National Health and Medical Research Council
Funding Amount
$620,967.00
Summary
The thymus is an organ dedicated to the production of crucial immune cells, called T lymphocytes. Cancer treatments, such as radiation or chemotherapy, destroy thymic function and impair immune recovery in patients. We aim to uncover molecular processes that govern the life and death decisions of cells in the thymus. Our goal is to then use this information to develop treatments to protect this critical organ from damage and improve immune recovery following radiation or chemotherapy.
T-follicular Helper Cell Subtypes That Induce Protective Anti-malaria Antibodies
Funder
National Health and Medical Research Council
Funding Amount
$431,000.00
Summary
Malaria causes significant disease burden globally. Currently there are no malarial vaccines that are suitable for widespread use. The development of effective vaccines is hampered by limited understanding of how the human immune system fights malaria. This project will use human samples collected to investigate how human blood cells activate the immune system to fight malaria. This research will identify avenues to improve the design of malaria vaccines in the future.
Quantifying the adaptive immune response. The aim of this project is to develop mathematical models and computer software capable of predicting immune responses in infection and disease. The ability to predict immune responses should allow better vaccine design and better understanding of what causes the immune system to attack its own body, causing autoimmune disease, or fail to respond, causing immunodeficiency. The models and software will also be applicable to other areas of cell biology, ....Quantifying the adaptive immune response. The aim of this project is to develop mathematical models and computer software capable of predicting immune responses in infection and disease. The ability to predict immune responses should allow better vaccine design and better understanding of what causes the immune system to attack its own body, causing autoimmune disease, or fail to respond, causing immunodeficiency. The models and software will also be applicable to other areas of cell biology, such as describing growth and development. Thus, this project will lead to advances in understanding of fundamental biology, as well as potential improvements in treatments for a range of diseases.Read moreRead less