Molecular And Cellular Mechanisms Of Skeletal Disease Mediated By Plasma Cell Dyscrasias
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in add ....Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in addition to other skeletal tumors, and our strong background in both OC and osteoblast biology. MM is a hematological malignancy characterised by plasma cell dyscrasia, which typically causes progressive and severe destruction of the skeleton, with accompanying bone pain, fracture and finally, hypercalcaemia of malignancy. Two related diseases, MGUS and POEMS, have been chosen for study because of their key similarities and differences with MM, and are likely to shed new light on the activities of MM in the bone. MGUS does not cause identifiable bone defects, whereas POEMS can give rise to both osteolytic and osteosclerotic lesions. Comparison of these conditions will uniquely enable us to examine why these seemingly related neoplasms are able to mediate disparate skeletal disease states. Primarily, and since there are few curative therapies for MM at present, our proposed studies are designed to identify targets for therapy that will treat the most serious manifestation of this disease, namely its destruction of bone tissue.Read moreRead less
Regulation Of PML By E6AP: Implications For Tumour Development.
Funder
National Health and Medical Research Council
Funding Amount
$537,829.00
Summary
PML is a vital tumour suppressor, but little is known about its regulation. We established that PML levels are affected by another cellular protein E6AP. This study will define the mechanism by which E6AP influences PML. Human cancers will be screened for the involvement of these proteins, to gain new insights into cancer onset. The intended practical outcome of these studies is to aid cancer diagnosis and provide new anti-cancer drugs.
CTL Avidity As A Determinant Of The Mature, Antigen-specific Immune Repertoire
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
Killer T lymphocytes are a diverse population which vary in their ability to recognise infected cells. This study aims to determine whether vaccine dose and frequency impact on the generation of highly sensitive killer T cells. This study will improve our basic knowledge of killer T lymphocyte selection during infection and have application to improved methods of vaccination.
THE ROLE OF A NOVEL NEGATIVE CELL CYCLE REGULATORY PATHWAY DURING ANIMAL DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are intereste ....Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, Drosophila. Central to the control of cell proliferation in all organisms are the Cyclin dependent protein kinases. Cyclin E-dependent protein kinase is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer causing mutations result in up-regulation of this critical cell cycle regulator and premature entry into the cell cycle. We have used a genetic approach using a weak mutation in Drosophila Cyclin E to isolate mutations in other important regulators of the G1 to S phase transition. This proposal focuses on one of these regulators, Phyl, and the proteins that function with it, Sina and Ebi, which act to target and lead to the degradation of key proteins that negatively regulate differentiation and that promote cell proliferation. In this proposal we seek to understand how the Ebi-Phyl-SIna protein complex functions to control cell proliferation in Drosophila. In addition, we will examine whether the Sina complex also acts to inhibit cell proliferation in the mouse. Due to the remarkable conservation of genes involved in cell proliferation control through evolution, this study is directly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
The Importance Of GM-CSF In Determining The Fate And Function Of Dendritic Cell (DC) Subsets: Resident DC, Inflammatory DC And Suppressive DC.
Funder
National Health and Medical Research Council
Funding Amount
$334,053.00
Summary
The hormone GM-CSF determines how infections are seen by the immune system GM-CSF is a hormone already in use for increasing the production of white blood cells. We have found that it also affects their function, especially that of specialised white blood cells that process infectious materials to be recognised by the immune system. This project aims to detail the effects of GM-CSF on specialised white blood cells.
Aldehyde-modified Antigens For The Immunotherapy Of Adenocarcinomas
Funder
National Health and Medical Research Council
Funding Amount
$284,250.00
Summary
The incidence of breast cancer in women is 1 in 8 and the frequency of other cancers are rising. Even with conventional approaches such as surgery, cytotoxic therapy, radiotherapy and combination therapy only a few cancers are treatable. The development of a cancer vaccine will greatly benefit humanity similar to childhood and adult vaccinations for preventing infectious disease. In this proposal we intend to chemically modify a synthetic protein called mucin 1 (MUC1) which is exprssed on cells ....The incidence of breast cancer in women is 1 in 8 and the frequency of other cancers are rising. Even with conventional approaches such as surgery, cytotoxic therapy, radiotherapy and combination therapy only a few cancers are treatable. The development of a cancer vaccine will greatly benefit humanity similar to childhood and adult vaccinations for preventing infectious disease. In this proposal we intend to chemically modify a synthetic protein called mucin 1 (MUC1) which is exprssed on cells in breast cancer to make it more immunogenic - that is make it look more like a foreign protein so that the immune cells can make antibodies or killer cells that recognise it. These activated cells can now migrate to the tumour sites and kill the invading tumour. In order to do this we are going to introduce mannose, a particular sugar that can bind to important white blood cells and an aldehyde group that can activate immune cells. We will test the effectiveness of the modified proteins in mice to see if they can generate an good immune. If this is satisfactory then we will see if mice are vaccinated with these modified proteins can reject implanted mouse or human tumours. If these experiments are successful further work can be done with human cells and later clinical trials. Any methods developed here will be applicable to other cancers and also infectious diseases.Read moreRead less
Identification Of Novel ERBB2 Co-operating Tumor Suppressors Using In Vivo RNAi Screens.
Funder
National Health and Medical Research Council
Summary
Invasive breast cancer is often lethal, however, noninvasive disease has a >98% survival rate. Thus, understanding how breast cancer develops invasive ability is an important research goal. Using a new method in mice predisposed to breast cancer, we will find genes that prevent tumor invasion and determine if they are important in human cancer. By understanding how these genes restrict tumor invasion, we hope to develop therapies to improve breast cancer treatment.
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.
Activated Protein C Suppresses The Abnormal Immune Response In Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$380,558.00
Summary
This project will determine whether activated protein C (APC) reduces the severity of rheumatoid arthritis (RA) by altering the abnormal response of a type of white blood cells known as the T cells. Experiments will utilise T cells isolated from patients with RA, normal controls and an animal model of RA, to examine a newly discovered immune pathway now thought to play a major role in causing RA. The results will help clarify whether and how APC prevents joint destruction in RA