Studying precancerous stem cells that cause T cell leukaemia. Recent research has identified abnormal stem cells that are the cause of T cell leukaemia. They are also resistant to therapeutics suggesting that they could be a cause of relapse. The aim of this project is to determine the abnormal pathways that cause these cells to become immortal and to determine new therapeutic strategies to eliminate them.
Zbtb11 is a druggable protein that is mis-expressed in blood cancers - second biggest cause of cancer death in Australia - and liver cancer, third leading cause of death from cancer worldwide. We have found that it interacts with 2 other proteins with potential roles in these diseases. Our studies examine the nature of these Zbtb11-partner interactions and their particular consequences for blood disorders. Zbtb11 contributions to disease development will be a target for novel disease therapy.
Bioreactors for manufacture of human platelets. Blood cell transfusion is a critical part of medicine that is supported by volunteer donors. Unfortunately, the demand for blood cells for transfusion far outstrips supply and therefore new strategies are required for manufacture of blood cells. This project will lead to the development of technology for manufacture of human platelets from stem cells. The systems devised will be applicable to a broad range of other blood cell types.
My research focuses on understanding the molecular regulation of blood cell production and function in health and disease with the ultimate goal of discovery of new treatments for blood cell diseases including leukaemia and autoimmunity.
The Role Of Med12, A Subunit Of RNA Polymerase II Mediator, In Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$495,490.00
Summary
In a screen of zebrafish for mutations in blood cell development, we isolated a mutant called syrah. The mutation causing the blood defect was identified in a gene called med12, which encodes a component of the RNA transcription machinery in cells. To understand how this mutation causes a reduction in blood cells, we will identify the proteins that interact with the med12 protein. Understanding the pathway involved may lead to the discovery of new causes of human congenital blood diseases.
Is Hypoxia Inducible Factor 2 The Trigger Of The Angiogenic Switch And A Driver Of Disease Progression In Myeloma?
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
Multiple myeloma (MM) is a fatal cancer of plasma cells (PC). PC migrate to the bone marrow, which compared with other organs is low in oxygen (hypoxic). In response to this hypoxia, the cancer cells turn on the expression of genes called hypoxia-inducible factors (HIF). HIFs activate the expression of genes that encourage blood vessel formation, which in turn stimulates greater tumour growth and disease progression. This proposal will investigate the role of HIFs in the progression of MM.
Platelet Receptor Regulation In Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$507,536.00
Summary
In response to bleeding, blood platelets use receptors to form a thrombus (blood clot) and block further loss of blood and aid tissue repair. People treated with heparin prior to surgery, can form autoantibodies that attack platelets, leading to thombus and thrombocytopenia (dangerous loss of circulating platelets). This is a significant clinical problem that is difficult to diagnose. We will determine how platelet receptor shedding can aid the diagnosis of heparin-induced thrombocytopenia.
Antibody-mediated Dendritic Cell Depletion To Attenuate GVHD
Funder
National Health and Medical Research Council
Funding Amount
$434,510.00
Summary
Not all patients with leukemia will be cured by chemotherapy. Stem cell transplantation improves their chances of survival. Stem cell transplantation requires intensive chemotherapy and radiotherapy to eradicate the underlying disease and infusion of healthy stem cells to provide an anti-leukemic effect and normal blood cells. Recovery from transplantation is not straightforward. Recovery can be hampered by the immunological reaction of the donor cells against the patient (Graft versus Host Dise ....Not all patients with leukemia will be cured by chemotherapy. Stem cell transplantation improves their chances of survival. Stem cell transplantation requires intensive chemotherapy and radiotherapy to eradicate the underlying disease and infusion of healthy stem cells to provide an anti-leukemic effect and normal blood cells. Recovery from transplantation is not straightforward. Recovery can be hampered by the immunological reaction of the donor cells against the patient (Graft versus Host Disease [GVHD]), despite immunosuppression. GVHD produces serious damage to the internal organs and lining of the mouth and gut. Recovery can also be circumvented by leukemic relapse. GVHD is associated with an increased risk of death and dying after transplantation. To date therapy for GVHD has relied on eliminating the T cells that cause the disease. However for T cells to cause damage they must first be primed with antigen presented on activated dendritic cells. The intensive conditioning therapy required to eradicate the underlying disease before transplantation also activates dendritic cells. Our project seeks to investigate the effects of lethal and non-lethal conditioning on dendritic cells with the aim of validating the use of antibodies designed to deplete activated dendritic cells as therapy for graft versus host disease.Read moreRead less
Identification Of The Molecular Genetic Basis Of The Hepatic Veno-occlusive Disease With Immunodeficiency Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight fam ....One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight families have been described in whom a number of individuals have succumbed to a condition which is clinically and histologically indistinguishable from VOD. Affected individuals also have a form of immunodeficiency (hence termed VODI), and the abnormalities are inherited in an autosomal recessive pattern. All eight are of Lebanese origin, suggesting that a single genetic ancestral mutation was responsible for the disorder in all families, who are distantly related. We have access to genetic material from three of these families, and are on the way to identifying the causative genetic abnormality. We hypothesise that understanding this abnormality will lead to an understanding of VOD which occurs after bone marrow transplantation. We have used 800 polymorphic genetic markers scattered throughout the genome to identify the location of the genetic abnormality, and have localised the defect to a region of chromosome 2 which contains approximately 37 known and predicted genes. We now aim to determine which of the gene(s) in the candidate region is responsible for VODI, and plan to examine DNA from individuals who have had VOD after transplantation to determine if they have a related abnormality. Finding the VODI gene will benefit these families through the availability of carrier detection and may also lead to an understanding of the veno-occlusive disease that occurs after bone marrow transplantation.Read moreRead less