A Transcription Factor Network Constraining The Development Of B Cell Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$617,531.00
Summary
B cell leukemias are relatively common, often aggressive hematopoietic malignancies and their cause is unknown in many cases. We have found that deficiencies in several transcription factors that normally control B cell differentiation cause B cell leukemias at a high frequency. We wish to identify the key pathways that are regulated by these factors and, in normal cells, prevent leukemic transformation. This will help to identify potential targets for therapeutic intervention.
Regulated Targeting Of Cell Death Effectors To And From Mitochondria.
Funder
National Health and Medical Research Council
Funding Amount
$302,764.00
Summary
The protein components of human cells travel to their appropriate intracellular homes by means of the targeting signals they carry. It now seems that a short, but important, list of key regulatory proteins are victims of protein hijacking: these proteins provide critical functions within a particular sub-cellular compartment, but are initially prevented from finding their way to this intracellular home. Only in response to specific physiological signals are these proteins released to find the si ....The protein components of human cells travel to their appropriate intracellular homes by means of the targeting signals they carry. It now seems that a short, but important, list of key regulatory proteins are victims of protein hijacking: these proteins provide critical functions within a particular sub-cellular compartment, but are initially prevented from finding their way to this intracellular home. Only in response to specific physiological signals are these proteins released to find the site at which they act. Human cells carry a molecular death-wish. A specific set of genes encode factors (proteins) that would ensure cellular suicide, or programmed cell death, but this program is only turned on in response to precise environmental signals. Because of the potentially deadly nature of these proteins, several of them are subject to protein hijacking thereby neutralizing their ability to promote cell death. These cell death factors are of great interest, and understanding their location and relocation within cells is crucial, as they represent targets for novel chemotherapies. Selectively triggering a cellular suicide has been proposed as a sensitive means to preventing the uncontrolled cell proliferation at the heart of many cancers. We are studying a set of key regulatory proteins to determine how and when they find their way to the intracellular homes and how this targeting effects their function in programmed cell death.Read moreRead less
Regulation Of PtdIns(3,4)P2 Signalling By Inositol Polyphosphate 4-phosphatase-1
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
Summary
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. One of the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has been implicated in many different human cancers which occur when cells divide uncontrollably and invade into the surrounding tissues. We have idenitified a novel enzyme called the inositol polyphosphate 4-phosphatase that appears to regulate cell proliferation and differentiation.
Understanding Transcription Factor Interactions In Blood Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
All blood cells develop from the same parent cells, which are known as stem cells. Once the decision is made for a stem cell to develop into a particular type of blood cell, mechanisms must exist that ensure the cell only expresses the genes that are appropriate for that cell type. These mechanisms involve the action of proteins known as transcription factors, which specifically activate the expression of the correct genes. While deregulation of these control mechanisms often leads to diseases s ....All blood cells develop from the same parent cells, which are known as stem cells. Once the decision is made for a stem cell to develop into a particular type of blood cell, mechanisms must exist that ensure the cell only expresses the genes that are appropriate for that cell type. These mechanisms involve the action of proteins known as transcription factors, which specifically activate the expression of the correct genes. While deregulation of these control mechanisms often leads to diseases such as cancer, unfortunately our understanding of how networks of transcription factors combine to direct processes such as blood cell development is relatively poor. GATA-1 and PU.1 are essential for the normal development of erythroid and myeloid blood cell types, respectively, and the work in the present proposal is aimed at understanding some of the molecular details of how direct interactions between these two proteins modulate their activity. This information should prove useful in understanding other transcriptionally regulated systems and may eventually help provide a route to treating a number of classes of blood cancer.Read moreRead less
The Role Of Dendritic Cells In Graft-versus-host Disease After Allogeneic Stem Cell Transplantation.
Funder
National Health and Medical Research Council
Funding Amount
$317,633.00
Summary
Allogeneic bone marrow transplantation (BMT) remains the most effect curative treatment for patients with a number of malignant conditions, especially leukemia. Graft-versus-Host Disease (GVHD) ocurrs when the newly transplanted bone marrow (which includes the immune system) recognises the transplant recipient as foreign and mounts an immune attack against patient tissues. GVHD is the major complication of BMT and is responsible for the death of up to half of the patients who receive this proced ....Allogeneic bone marrow transplantation (BMT) remains the most effect curative treatment for patients with a number of malignant conditions, especially leukemia. Graft-versus-Host Disease (GVHD) ocurrs when the newly transplanted bone marrow (which includes the immune system) recognises the transplant recipient as foreign and mounts an immune attack against patient tissues. GVHD is the major complication of BMT and is responsible for the death of up to half of the patients who receive this procedure. Research to date by Dr Hill and colleages has provided substantial detail on how and why this process occurs. This information has led to a number of advances in the field which are already improving patient survival after BMT. This includes a new type of bone marrow transplantation that uses a naturally ocurring growth factor (called a cytokine) to allow the collection of immature bone marrow cells from the blood of transplant donors. The transplantation of these cells rather than bone marrow appears to reduce the chance of dying during BMT and also improves the cure rates from the underlying leukemia. In addition, Dr Hill has developed a novel method for preventing GVHD using different types of naturally ocurring growth factors called cytokine shields that help protect patient tissue from attack by the immune system. It has recently become clear that the immune system is directed by a subtype of white cells called dendritic cells and Professor Hart at the Mater Medical Research Institute has been a pioneer in this field. As initiators of the immune system it is likely that dendritic cells play a pivotal role in GVHD and Dr Hill and Prof Hart at the Mater Medical Research Institute will study DC within the context of Dr Hills newly developed therapies with the aim of further understanding the processes of GVHD. This work will allow manipulation of these cells during BMT in order to improve patient survival.Read moreRead less
Bone marrow transplantation (BMT) is the most effect treatment for a number of conditions, especially leukemia. Graft versus host disease (GVHD) is a complication of BMT and results in the death of up to 50% of transplant recipients. GVHD occurs when the newly transplanted immune system recognizes the recipient as foreign and mounts and immune reponse against the patients tissues. These studies will focus on identifying and understanding the function of the immune cells which drive GVHD.
Cancer is the result of multiple genetic errors, involving both the overactivity of growth-stimulating oncogenes and the loss of tumour suppressor genes. The identification of the genes in both of these categories is important if we are to understand and intervene in the disease. Tumour suppressors are the more difficult to identify, precisely because they are lost in cancer cells. Normally the task is extremely time consuming, tedious and expensive. We have developed a system which will provide ....Cancer is the result of multiple genetic errors, involving both the overactivity of growth-stimulating oncogenes and the loss of tumour suppressor genes. The identification of the genes in both of these categories is important if we are to understand and intervene in the disease. Tumour suppressors are the more difficult to identify, precisely because they are lost in cancer cells. Normally the task is extremely time consuming, tedious and expensive. We have developed a system which will provide a short-cut to the cloning of one such gene. We have started with the mouse version, which is lost in leukemic cells. We have mapped the gene to within a very small chromosomal region, and we have identified a biological effect which correlates with loss of the gene. Our next step is to combine these two approaches to clone the gene. Because these genes are always highly conserved between species, we will be able to quickly clone the corresponding human gene, the loss of which is very likely to be important in cancer of various types.Read moreRead less
Molecular Analysis Of Myelodysplasia In The Nup98HoxD13 Mouse Model
Funder
National Health and Medical Research Council
Funding Amount
$351,502.00
Summary
Myelodysplastic syndrome is a preleukemic condition which is poorly understood and occuring at an increasing frequency. Unfortunately no targeted therapy exists. Two features of the disease are abnormal gene expression and abnormal cell death. We have a uniquely accurate model of this disease, and we plan to use it to investigate these two phenomena which will lead to greater understanding of the disease and new molecular targets for therapeutic agents to be developed and tested in our model.
Biomarker-driven Applications Of Immunotherapy In Lymphoma
Funder
National Health and Medical Research Council
Funding Amount
$189,384.00
Summary
Immunotherapy is a new treatment strategy that works in many different lymphoma types but there is no successful method of predicting response or selecting patients. I aim to explore use of immunotherapy in 3 key lymphoma subtypes to identify new techniques for predicting which patients respond to treatment through prospective biomarker research using novel techniques. These aims will be achieved through a series of clinical trials of immunotherapy in lymphoma all with a biomarker research focus
Mechanisms Of Action Of The Antigen Presenting Cells That Impair Lymphoma-specific Cytotoxic T Lymphocytes
Funder
National Health and Medical Research Council
Funding Amount
$295,983.00
Summary
Our immune systems are continually fighting cancer. However, the cancer cells occasionally acquire mutations that enable them to subvert the immune system. Usually they do this by hiding under the appearance of normal tissue, but sometimes they activate the very mechanisms that are in place to shut-down immune responses when these are no longer necessary. The goal of this proposal is to identify such mechanisms and find ways of bypassing them, thus restoring anti-tumour activity in patients.