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Determining The Molecular Basis Of Therapy Resistance Conferred By Genetic Lesions In The Tumour Protein TP53 In Haematological Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$885,183.00
Summary
Blood cancers that have genetic lesions in a tumour suppressor protein called TP53 respond poorly to therapy. Curing these patients is extremely challenging and new therapeutic strategies are desperately needed. Here, we aim to uncover the molecular mechanisms of drug resistance caused by loss of TP53 function and rationally design new therapies that may be curative. To do this, our team of leading scientists and clinicians will study patient samples and pre-clinical models of blood cancer.
Tumour B-cells From Lymphomas Are Resistant To ATP-mediated Apoptosis Due To Non-functional P2X7 Receptors
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Adenosine triphosphate (ATP) is an important constituent normally present inside cells. When added to normal lymphocytes (or released by cells lining the vessel wall or in lymph nodes), ATP acts from outside these cells to open a pore as well as activate an enzyme which digests the lipid envelope of the cell. This loss of lipid covering of the cell produces a leakiness to various constituents of the cell which gradually leads to death of normal lymphocytes. However in the malignant lymphocytes o ....Adenosine triphosphate (ATP) is an important constituent normally present inside cells. When added to normal lymphocytes (or released by cells lining the vessel wall or in lymph nodes), ATP acts from outside these cells to open a pore as well as activate an enzyme which digests the lipid envelope of the cell. This loss of lipid covering of the cell produces a leakiness to various constituents of the cell which gradually leads to death of normal lymphocytes. However in the malignant lymphocytes of human lymphomas this mechanism of cell death does not operate. The loss of function of this 'death receptor' explains why in the lymphomas there is a progressive accumulation of malignant lymphocytes which give enlargement of lymph nodes and spleen and leads to death of the patient. Knowledge of the defect in this pathway of cell death will enable new strategies to be introduced to control this malignant disease.Read moreRead less
The Role Of The Pro-survival Bcl-2 Family Member A1 In The Development And Sustained Growth Of Lymphomas.
Funder
National Health and Medical Research Council
Funding Amount
$628,459.00
Summary
The death of cells, which is regulated by a complex interaction between cell survival and killer proteins, is an important mechanism to prevent cancer. In this proposal we aim to understand the function of one of the cell survival proteins in cancer development and maintenance. This will help to develop novel therapeutic drugs specifically targeting this cell survival protein, thereby eliminating specifically the cancer cells and minimizing collateral damage of healthy tissues.
A Novel Approach For Treating B-cell Lymphoma By Inhibition Of The E3 Ligase E6AP
Funder
National Health and Medical Research Council
Funding Amount
$624,846.00
Summary
B-cell lymphoma is the most common type blood cancer diagnosed in Australia, and Australia's fifth most common cancer. Despite remarkable advances in diagnosis and treatment, lymphoma continues to rank as a leading cause of cancer-related mortality. Our pilot studies reveal a novel approach to treatment of B-cell lymphoma by inhibiting an enzyme that destroys our natural mechanism of defense against cancer. In this study we will test the efficacy of this novel treatment.
A major feature ofcancer is accelerated cell growth and proliferation. One of the major rate-limiting processes that regulates cell growth is the synthesis of ribosomes (the protein synthetic machinery). This study will examine a factor termed UBF whose activity is critical for the regulation of ribosome synthesis. It wll also explore the hypothesis that dysregulation of ribosome biogeneis underlies and contributes to the aetiology of many human cancers.
The Regulation And Differentiation Potential Of Human Memory B Lymphocytes
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Antibody produced by our immune system plays a critical role in protecting us from infectious disease. Remarkably our ability to make antibodies is much faster the second time we see the infection. This memory of the previous attack occurs due to the formation of memory B cells that circulate in the blood, sometimes for years, looking for the same intruders. If they detect the infection they rapidly become activated and remake the antibody. These memory cells are very important for our protectio ....Antibody produced by our immune system plays a critical role in protecting us from infectious disease. Remarkably our ability to make antibodies is much faster the second time we see the infection. This memory of the previous attack occurs due to the formation of memory B cells that circulate in the blood, sometimes for years, looking for the same intruders. If they detect the infection they rapidly become activated and remake the antibody. These memory cells are very important for our protection. Vaccines operate by tricking the immune system into making these memory cells, even though the body hasn't seen the actual disease. Although clearly vital for our health little is known about the activation and antibody production by human B memory cells. This project will redress our lack of knowledge by performing a comprehensive evaluation of the properties of this important cell type.Read moreRead less
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.
Cell Pedigree Tracking To Elucidate How Polarity Proteins Alter Fate In B-cell Development And Leukaemia.
Funder
National Health and Medical Research Council
Funding Amount
$307,946.00
Summary
During the onset of cancer, the orientation of cells is lost. My research project aims to determine the cellular and molecular basis by which proteins responsible for the orientation of cells are involved in leukaemia. Additionally, my work will investigate whether or not all proteins are equally distributed during cell division in B cell development, and will provide a platform for further investigation into how protein distribution might orchestrate fate decisions during development and leukae ....During the onset of cancer, the orientation of cells is lost. My research project aims to determine the cellular and molecular basis by which proteins responsible for the orientation of cells are involved in leukaemia. Additionally, my work will investigate whether or not all proteins are equally distributed during cell division in B cell development, and will provide a platform for further investigation into how protein distribution might orchestrate fate decisions during development and leukaemia.Read moreRead less
Antigen Receptor As Oncogene: Understanding CARD11 Mutations In B Cell Malignancy
Funder
National Health and Medical Research Council
Funding Amount
$607,395.00
Summary
More than 5000 Australians are newly diagnosed as lymphomas. Recent technology identified many candidate genes for lymphomas, however it still remains unclear how each mutated gene distorts signalling molecules inside tumours cells. By introducing one of recurrent mutated genes, CARD11 into mouse B cells, we will examine how this mutation affects normal signalling pathways and B cell functions. We hope this project will provide a guidance to use forthcoming drugs to target specific molecules.