Development And Function Of NKT Cell Subsets In Humans
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
NKT cells are a type of white blood cell that help to control the function of the immune system. Many studies have reported an association between low NKT cell levels and increased rates of cancer and autoimmune diseases such as type 1 diabetes (T1D). Unfortunately, NKT cells are a relatively recent discovery and their function is not well understood, especially in humans. For example, it has only recently been discovered that there are different types of NKT cells with different functions. This ....NKT cells are a type of white blood cell that help to control the function of the immune system. Many studies have reported an association between low NKT cell levels and increased rates of cancer and autoimmune diseases such as type 1 diabetes (T1D). Unfortunately, NKT cells are a relatively recent discovery and their function is not well understood, especially in humans. For example, it has only recently been discovered that there are different types of NKT cells with different functions. This lack of knowledge has prevented us from understanding how NKT cells normally prevent disease, and how we should treat diseases associated with low NKT cell numbers. In this project, we will study human NKT cells to determine how many different subsets exist, how they develop, and what role they play in the immune system. Importantly, we will use our knowledge to compare NKT cells from healthy donors and patient groups with T1D and cancer to determine exactly what is wrong with the NKT cells in these people. While both diseases are already linked to low NKT cell numbers, we do not know how these problems arise, or if some types of NKT cells are more important than others. Our study will determine how different types of NKT cells develop and function in humans and therefore allow a much more detailed understandng of how to diagnose and treat NKT cell deficiencies associated with different diseases.Read moreRead less
NKT cells are a type of lymphocyte with the ability to prevent a broad range of diseases including cancer, autoimmunity, infection and graft rejection. Sometimes, NKT cells also cause diseases, including allergy and atherosclerosis. Therefore, the ability to modulate these cells an important health objective. This project will investigate how NKT cells become activated by studying their surface receptors and what these receptors interact with.
Allogeneic stem cell transplantation (SCT) remains the most effect curative treatment for patients with a number of malignant conditions, especially leukemia. The ability to cure leukemia by this procedure relates to a process known as Graft-versus-Leukaemia effects (GVL) which ocurrs when the newly transplanted stem cells (which includes the immune system) recognises the leukemia as foreign and mounts an immune attack against it. These studies will focus on the effect of a cellular pathway invi ....Allogeneic stem cell transplantation (SCT) remains the most effect curative treatment for patients with a number of malignant conditions, especially leukemia. The ability to cure leukemia by this procedure relates to a process known as Graft-versus-Leukaemia effects (GVL) which ocurrs when the newly transplanted stem cells (which includes the immune system) recognises the leukemia as foreign and mounts an immune attack against it. These studies will focus on the effect of a cellular pathway invilving NKT cells that preliminary data suggests is critical to the development of GVL. Methods to augment this activation pathway will be studied in preclinical models that may then be studied in clinical trials with the aim of improving the outcome of patients transplanted for leukemias.Read moreRead less
A Congenic Approach To Analysing The Genomic Control Of Innate Immunity In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$240,156.00
Summary
In addition to the lymphocytes, which are specialised white cells that can learn to defeat the infections that the body has been previously exposed, the body has a number of other defences. These non-learning systems have been honed by evolution and usually form an effective first-line of defence. This proposal deals with three: complement, and two highly specialised types of white blood cell, the Natural Killer cells and the NKT cells. The project will study mice especially bred to carry differ ....In addition to the lymphocytes, which are specialised white cells that can learn to defeat the infections that the body has been previously exposed, the body has a number of other defences. These non-learning systems have been honed by evolution and usually form an effective first-line of defence. This proposal deals with three: complement, and two highly specialised types of white blood cell, the Natural Killer cells and the NKT cells. The project will study mice especially bred to carry different versions of the genes which control these defences. Particular attention will be paid to their involvement in the autoimmune diseases, type 1 diabetes and lupus.Read moreRead less
Molecular Control Of Cell Proliferation In Early Mouse Development
Funder
National Health and Medical Research Council
Funding Amount
$338,009.00
Summary
Elucidation of cell cycle regulation in the proliferating pluripotent cells of the early mammalian embryo is likely to have important impact on basic scientific knowledge, and on the development of novel therapeutic strategies. Investigation of this problem, in vitro and in vivo, requires specialist skills in cell cycle analysis, and experimental manipulation of mammalian embryos and pluripotent cells. This application will seek to address these fundamental issues of early development and cell p ....Elucidation of cell cycle regulation in the proliferating pluripotent cells of the early mammalian embryo is likely to have important impact on basic scientific knowledge, and on the development of novel therapeutic strategies. Investigation of this problem, in vitro and in vivo, requires specialist skills in cell cycle analysis, and experimental manipulation of mammalian embryos and pluripotent cells. This application will seek to address these fundamental issues of early development and cell proliferation using molecular approaches. The general aims will be: 1. to obtain a detailed description of cell cycles in pluripotent and differentiating cells of the mouse embryo 2. use this information to build a molecular description of cell cycle events during early embryogenesis 3. investigate the relationship between rapid cell proliferation in the embryo and pluripotencyRead moreRead less
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in general, to maintain the correct number of cells in the body. As such, misregulation of apoptosis is associated with the pathogenesis of a wide array of diseases. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases called caspases, that target many cellular proteins for specific cleavage. The activation of caspases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. If we understand how these regulatory mechanisms operate, we can then formulate strategies that are targeted towards pathologies involving abnormal apoptosis. In this proposal we will use vinegar fly as a model to study the function of caspases in development. We believe that results from this proposal will have several major benefits. Firstly, they will provide important insight into the mechanisms of developmental apoptosis thereby filling many gaps in our current knowledge. Secondly, the study will endeavour to identify new molecules-pathways that lead to caspase activation. Finally, the proposed studies will shed light on the function of caspases in non-apoptotic pathways.Read moreRead less
Understanding how the brain grows and is organised is one of the great challenges of science. This project seeks to identify key regulators of neural progenitors as these are the building blocks from which all brains cells are derived. This knowledge may also identify new avenues through which to manipulate neural progenitor function. This has implications not only for normal brain development but also potential therapies for neural disorders and disease.
This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does ....This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does not achieve this through changing genetics the library always stays intact. Rather, it acts by using proteins or chemicals to make DNA functional in one way, or another. Genomic imprinting is a special type of epigenetics. While an embryo has received identical genetic information from each of its parents, the epigenetic information received from each parent was not entirely the same. Some genes which behave differently according to what parent they came from. For example, a gene that makes a growth factor protein is active only if received from the father. If received from the mother, it is inactive, and makes no protein. Genes behaving in this way are known as imprinted genes. We are trying to discover what epigenetic mechanisms are behind this behaviour of imprinted genes. One way we are approaching this problem is to study germ cells the cells giving rise to eggs and sperm. These cells are unusual in that their imprinted genes behave in the same way regardless of whether they were received from the mother or father, i.e., like any other gene. If we can understand why this is the case, we will be better able to understand why imprinted genes behave the way they do in the rest of the cells of the body. Broadly, the mechanisms we uncover should further our understanding of germ cell development, gene expression, and disease. Perturbations in the epigenetic profile are likely causes of human disease, including cancer.Read moreRead less
The Function Of Transcription Factor SCL In T Cell Development.
Funder
National Health and Medical Research Council
Funding Amount
$504,750.00
Summary
SCL is a gene which is abnormally expressed in a large percentage of human T cell leukaemias. Mouse models that increase SCL levels have demonstrated that T cell maturation is abnormally affected by SCL. Thus, providing a clue as to how T cell leukemias arise. By utilising recombinant DNA technology we are now able to control SCL levels in T cell maturation. We can either increase the level of SCL using pharmacological reagents or we can genetically remove SCL from maturing T cells. This double- ....SCL is a gene which is abnormally expressed in a large percentage of human T cell leukaemias. Mouse models that increase SCL levels have demonstrated that T cell maturation is abnormally affected by SCL. Thus, providing a clue as to how T cell leukemias arise. By utilising recombinant DNA technology we are now able to control SCL levels in T cell maturation. We can either increase the level of SCL using pharmacological reagents or we can genetically remove SCL from maturing T cells. This double-edged approach will allow us to monitor the effects of SCL on maturing T cells with a precision that has never previously been achieved. Results from this approach will provide new insights into how T cell leukaemia develops and provide the foundation for new rational based treatments.Read moreRead less
Functional Genomic Analysis Of NK And NKT Cell Immune Control Of Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
The major populations of white blood cells responsible for learned immunity to are the B cells, which make antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells produce antibody. The T and B cells occasionally attack the body s own tissues, resulting in autoimmune disease. These diseases include type 1 diabetes, lupus, and anaemia, and collectively represent the third commonest cause of morbidity and mortality in humans. The major reas ....The major populations of white blood cells responsible for learned immunity to are the B cells, which make antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells produce antibody. The T and B cells occasionally attack the body s own tissues, resulting in autoimmune disease. These diseases include type 1 diabetes, lupus, and anaemia, and collectively represent the third commonest cause of morbidity and mortality in humans. The major reason why autoimmunity occurs is thought to be due to a failure in the mechanisms responsible for controlling such unwanted responses. Two other populations of white blood cells are involved in this regulation, termed NK and NKT cells, each of which release important cell hormones. The current project is designed to test whether defects in NK and NKT cells lead to autoimmune disease. For this purpose a special strain of mice (NOD mice) will be used. The reasons for their selection are: 1) they are highly susceptible to a range of autoimmune diseases including diabetes, lupus and anaemia, and 2) we and others have found that they are deficient in both NK and NKT cells. The proposed experiments are divided into two groups, one designed to characterise the nature of the defects in these cells and the other to identify the genes responsible for them. In this way it should be possible to shed light on the genetic basis of autoimmune diseases in general. The approach to be used involves sophisticated techniques of genetic analysis, which require production of special congenic lines of mice. These mice are like NOD mice but carry in addition to NOD genes genetic regions from a non-autoimmune strain with the potential to correct the defects in NK and NKT cells. In this way, it should be possible to pinpoint the disease susceptibility genes involved in causation of autoimmunity and to work out how they affect NK and NKT cells.Read moreRead less