Determining The Role Of Rel/NF-kB Transcription Factors In Myeloid Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$500,944.00
Summary
Different types of mature blood cells arise from stem cells in a process involving changes in gene expression that dictate which types of blood cells ultimately develop. A family of gene regulatory proteins called NF-kB transcription factors has been found to control the pattern of gene expression in a particular blood cell precursor called a granulocyte macrophage precursor (GMP) that normally generates two types of mature blood cells called macrophages and neutrophils. In the absence of NF-kB ....Different types of mature blood cells arise from stem cells in a process involving changes in gene expression that dictate which types of blood cells ultimately develop. A family of gene regulatory proteins called NF-kB transcription factors has been found to control the pattern of gene expression in a particular blood cell precursor called a granulocyte macrophage precursor (GMP) that normally generates two types of mature blood cells called macrophages and neutrophils. In the absence of NF-kB proteins, a change in the pattern of gene expression in GMPs leads to an imbalance in production of these two blood cell types that now favours the generation of neutrophils. This work will provide insight into the molecular mechanisms of blood cell development regulated by NF-kB. With disturbances in the balance of blood cell formation representing a hallmark of leukemia, understanding how this process is normally controlled may have important implications for developing therapeutic strategies to combat various types of leukemias.Read moreRead less
De-differentiation Of Committed Cells Into Haematopoietic Stem Cells By The Instructive Role Of The Transcription Factor HOXB4
Funder
National Health and Medical Research Council
Funding Amount
$683,040.00
Summary
Blood stem cells are long-lived and can give rise to every cell type of the blood system and due to these properties they are currently used in the clinics. Despite their importance, our knowledge of the mechanisms the control the multiplication of these rare cells is very scarce. This proposal aims to identify key factors that have the potential to convert mature, easy available blood cells into stem cells. This knowledge has to potential to lead to novel system that allow the expansion of stem ....Blood stem cells are long-lived and can give rise to every cell type of the blood system and due to these properties they are currently used in the clinics. Despite their importance, our knowledge of the mechanisms the control the multiplication of these rare cells is very scarce. This proposal aims to identify key factors that have the potential to convert mature, easy available blood cells into stem cells. This knowledge has to potential to lead to novel system that allow the expansion of stem cells for transplantations in the future.Read moreRead less
DNA damage response pathways play important roles in preventing the onset of cancer and regulating the clinical response to chemotherapeutics, and some of the relevant proteins have additional functions during normal development. This fellowship will study new a human protein with key roles in the formation of the lung, and its roles in preventing devastating consequences of normal oxidative damage to DNA, as well as additional fundamental mechanisms involved in preventing genome mutations.
Activation And Suppression Of Oncogenic Translocation By Uracil-DNA Glycosylases
Funder
National Health and Medical Research Council
Funding Amount
$513,000.00
Summary
The AID enzyme is implicated in cancer in B lymphocytes and prostate cells. AID causes DNA damage normally recognised by repair enzymes UNG and MutS?, among others. The repair processes these factors initiate involve a DNA break that, if incorrectly re-joined, destabilises the genome, causing cancer. Understanding the function of AID, UNG and MutS? in B cell lymphomas and prostate cancer will provide fundamental insights into cancer and may identify targets for new therapeutics.
Revealing How Transcription Factors Search The DNA To Control Preimplantation Development In Mammals
Funder
National Health and Medical Research Council
Funding Amount
$605,251.00
Summary
The development of mammalian embryos relies on proteins that bind to DNA to activate different genes. While several proteins regulating genes during embryonic development have been identified, it remains unknown how these proteins find their specific DNA targets. We will apply new non-invasive methods to analyse the movement of DNA–binding proteins in intact mouse embryos undergoing normal development, and will determine the molecular mechanisms that control DNA–protein interactions.
Regulation Of TNF Expression In Inflammation And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$728,447.00
Summary
By studying a spontaneous mutation in mice, we have found an error in the TNF gene (a major factor in many inflammatory diseases) that causes severe arthritis, heart valve disease and gut inflammation. We have also identified new regulators of TNF expression, which might be useful therapeutic targets to limit inflammation. We intend to study the role of these regulators in controlling the expression of TNF, and the link between chronic inflammation and the development of cancer.
The Role Of MOZ In The Development Of The Hematopoietic System, Spleen And Thymus
Funder
National Health and Medical Research Council
Funding Amount
$324,375.00
Summary
Current treatment of leukaemia in adults is unsatisfactory with the majority of patients dying. In the past most treatments for cancer have been empirical, that is a particular drug has been found to be effective by trial and error rather than a process of rational design. In order to improve the rate at which effective treatments for leukaemia are found it is necessary to understand how hematopoiesis is regulated and what the critical points are where things can go wrong, leading to cancer. Som ....Current treatment of leukaemia in adults is unsatisfactory with the majority of patients dying. In the past most treatments for cancer have been empirical, that is a particular drug has been found to be effective by trial and error rather than a process of rational design. In order to improve the rate at which effective treatments for leukaemia are found it is necessary to understand how hematopoiesis is regulated and what the critical points are where things can go wrong, leading to cancer. Some genes are commonly found to be mutated in leukaemia. Clearly these genes are involved in some key aspect of regulation of hematopoiesis. We are studying one of these genes, MOZ, which is mutated in acute myeloid leukaemia. The purpose of this grant is to determine what the normal function of this gene is. One of the most promising new treatments for leukaemia is directly targeting the regulation of gene expression inside the cell. MOZ is one of the proteins, which regulates gene expression in hematopoiesis and controls the differentiation of different types of blood cells. One of the possible effects of these new types of anticancer drugs is to accentuate the normal function of MOZ. However, at the moment we don't know what the normal function of MOZ is so it is impossible to test this prediction. If we know which pathways controlling blood formation MOZ is acting in it may be possible, in the future, to use this information to improve on the current anti cancer drugs in a more directed way than has been possible in the past.Read moreRead less
Expansion Of TGF-beta-Smad Signaling Network And Intrinsic Epithelial-mesenchymal-endothelial Transition
Funder
National Health and Medical Research Council
Funding Amount
$557,297.00
Summary
The majority of tumor death occurs due to tumor metastasis. Both tumor growth and tumor spread require angiogenesis, which is thought to be driven by tumor but originated from host endothelial cells. Could tumor cells behave and function like endothelial cells? This application aims to detect the transition of adult epithelial cells to endothelial cells through a transient mesenchymal state. Our studies should reveal both the molecular and cellular causes of vasculogenic mimicry, thus establishi ....The majority of tumor death occurs due to tumor metastasis. Both tumor growth and tumor spread require angiogenesis, which is thought to be driven by tumor but originated from host endothelial cells. Could tumor cells behave and function like endothelial cells? This application aims to detect the transition of adult epithelial cells to endothelial cells through a transient mesenchymal state. Our studies should reveal both the molecular and cellular causes of vasculogenic mimicry, thus establishing a new paradigm in understanding tumor growth and metastasis. Such novel molecular understanding will open up new anti-tumor therapeutic opportunities.Read moreRead less