OVARIAN CANCER METASTASIS: Unraveling The Biology Of The Plasminogen Activation Cascade
Funder
National Health and Medical Research Council
Funding Amount
$169,875.00
Summary
Ovarian cancer affects 1,200 new Australians every year. Compared to breast cancer where research education and early screening have improved mortality rates, the incidence of ovarian cancer has not improved and death rates have more than doubled since 1930. With few overt symptoms, ovarian cancer has an extremely poor prognosis - a staggering 71% of women diagnosed with ovarian cancer will die from the disease, compared to 21% for breast cancer. Any studies which increase our understanding of t ....Ovarian cancer affects 1,200 new Australians every year. Compared to breast cancer where research education and early screening have improved mortality rates, the incidence of ovarian cancer has not improved and death rates have more than doubled since 1930. With few overt symptoms, ovarian cancer has an extremely poor prognosis - a staggering 71% of women diagnosed with ovarian cancer will die from the disease, compared to 21% for breast cancer. Any studies which increase our understanding of the biology of ovarian cancer metastasis may lead to new therapies designed to control these processes - as such this would be a major inroad into our fight against this cancer. The aim of this novel research project is to unravel the role that one cell surface system (the plasminogen (Plg) activation cascade) plays in determining the ability of ovarian cancer cells to metastasise and regulate new tumour blood vessel formation. This study addresses the paradoxical observations that this cascade can simultaneously facilitate cancer metastasis whilst concomitantly stopping new blood vessel formation in tumours. Using a number of advanced molecular cell biology methods, the hypothesis we will test is that the capacity of ovarian cancer to metastasise is determined by differential processing of plasminogen subsequent to cell-surface Plg binding. This results in a delicate balance between the generation of cell surface proteases and the release of protein fragments capable of stopping tumour blood vessel growth. Our group is well-equipped to address this hypothesis since we have already shown that: (1) Plg binding and activation is required for cancer cell invasion; (2) Plg binding and activation is elevated on malignant compared to benign cancers (3) Plg unfolds after it binds to cell surfaces or recombinant receptors; and, (4) Plg is easily fragmented to products that inhibit new blood vessel formation after binding to some cancer cells.Read moreRead less
Characterisation Of The Molecular Mechanisms Of Abeta-induced Proteolysis Of The Neural Cell Adhesion Molecule 2 (NCAM2)
Funder
National Health and Medical Research Council
Funding Amount
$374,666.00
Summary
Neurons in the brain are connected by synaptic contacts. Amyloid beta peptide accumulating in the brain in Alzheimer’s disease destroys synaptic contacts by degrading synaptic cell adhesion molecules which maintain the structure of the contacts. The aim of the project is to characterise the molecular mechanisms of amyloid beta-dependent degradation of synaptic cell adhesion molecules. The project will identify strategies that can be used to inhibit synapse loss in Alzheimer’s disease.
Exploring The Role Of Arrcd4 In Extracellular Vesicle Biogenesis And Its Implications In Tissue Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$678,742.00
Summary
Most cells in the body release small packages known as extracellular vesicles (or EVs in short), which carry proteins and other cellular material. EVs transport important cellular messages required for the everyday function of cells and play crucial roles both in normal wellbeing and disease. This proposal will investigate how EVs are formed, how they select their protein content and how they contribute to the maturation of some cell types in the body.
Identification Of Orphan F-box Helicase Substrates And Their Role In Genomic Stability And Life Extension.
Funder
National Health and Medical Research Council
Funding Amount
$281,684.00
Summary
Within each cell proteins are synthesised and destroyed with delicate control to ensure the cell functions appropriately. Excess proteins are removed by specific degradation pathways, which are often misregulated in cancer. This project aims to further our understanding of misregulated protein degradation in cancer. The knowledge gained will assist with the development of cancer targeting drugs specific to protein degradation pathways that become misregulated in tumour formation.
A Novel Mechanism For Regulating Membrane Proteins By Ubiquitin Ligases And Their Adaptors
Funder
National Health and Medical Research Council
Funding Amount
$627,897.00
Summary
Many membrane proteins act as ion channels, transporters or receptors for extracellular ligands and are critical to normal functioning of the cell. These proteins are generally regulated by transport to or from the membrane to ensure that correct levels are maintained at the membrane. This proposal is to study a novel way of regulating membrane proteins. The successful completion of the work will provide important knowledge relevant to many human diseases.
Molecular Basis Of Artemisinin Action And Resistance In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$758,464.00
Summary
The malaria parasite, P. falciparum causes ~450,000 deaths each year. Resistance to the front-line antimalarial drug, artemisinin, is increasing, threatening at least another 100,000 lives per year, and potentially causing an additional ~A$500M in lost productivity. This project will identify the components of the parasite's cellular defence system that underpin resistance and will point to strategies for overcoming resistance to this important drug class.
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
Determining The Role Of Parkin And PACRG In Protein Turnover
Funder
National Health and Medical Research Council
Funding Amount
$555,780.00
Summary
Alterations in the parkin gene are associated with neurodegenerative disorders such as Parkinson's disease (PD). The aim of this proposal is to characterise the function of parkin and the role it plays in disease development. We will determine the role of parkin in the brain and how loss of this function causes specific nerve cells to die. These studies will provide the means to develop novel therapeutic approaches to alleviate or prevent these disorders.
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.