Recent evidence suggests that the Siah proteins are involved in sensing low oxygen levels in cells, and subsequently activating processes to help the cell survive under these conditions. Low oxygen conditions occur in cancer and sites of inflammation, suggesting that inhibiting Siah may improve patient outcomes in diseases such as cancer and arthritis. We aim to perform a high throughput screen for drugs that inhibit Siah protein function and to test these in cancer cells.
Investigation Of An LMO4- And BRCA1 -containing Complex Involved In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$440,250.00
Summary
Breast cancer will affect one in twelve Australian women and a quarter of those will die from breast cancer. At present we still know little about what causes the disease, and there is currently a lot of activity in the field of breast cancer research that will ultimately increase our ability to both detect its development at early stages and to provide effective treatments for the disease. We do know that losing the function of a few genes (breast cancer susceptibility genes) leads to a very hi ....Breast cancer will affect one in twelve Australian women and a quarter of those will die from breast cancer. At present we still know little about what causes the disease, and there is currently a lot of activity in the field of breast cancer research that will ultimately increase our ability to both detect its development at early stages and to provide effective treatments for the disease. We do know that losing the function of a few genes (breast cancer susceptibility genes) leads to a very high likelihood of developing cancer, and we know that the normal roles of the proteins that are produced from these genes are to prevent cancers from occurring in a spontaneous fashion. However, the inheritance of mutations in breast cancer susceptibility genes accounts for only a few percent of breast cancer cases. A recently discovered protein, known as LMO4, has been found at abnormal levels in over 50% of non-inherited breast tumors. This protein has been found to both interact with the protein from the most commonly occurring breast cancer susceptibility gene, known as BRCA1, and to prevent the normal activity of BRCA1. Thus, if we could develop reagents that prevent LMO4 from interacting with BRCA1, we could use those reagents as lead compounds for the development of anti-breast cancer drugs. Before we can develop such reagents we need to fully understand both what these proteins look like and how they interact. We already know that two other proteins, known as ldb1 and CtIP are involved in the LMO4:BRCA1 interaction. We will investigate the ways in which all of these proteins interact, from determining how strong each interaction is, to getting atomic level information about which surfaces of the proteins make the most contribution to each interaction. This should let us identify good targets for the design and development of anti-breast cancer drugs.Read moreRead less
Role Of FHA Domains As Protein-protein Interaction Modules In Cell Signalling
Funder
National Health and Medical Research Council
Funding Amount
$191,973.00
Summary
The proper processing of information in cells involves the association of different proteins to signalling complexes. We will decipher the role the so-called FHA module plays in the formation of protein complexes. FHA modules are present in several proteins that are important for the repair of damaged DNA and the stability of chromosomes. Understanding the structure and function of this module will be relevant for various forms of cancer where DNA is damaged.
The HIV-1 Tat Protein Is An Reverse Transcription Co-factor.
Funder
National Health and Medical Research Council
Funding Amount
$404,592.00
Summary
HIV-1 is the virus that causes AIDS. In order for HIV-1 to grow, the viral genetic material must be converted into a form that is compatible with a human host. Specifically, the HIV-1 genetic material is made of RNA while the human genome is composed of DNA. An HIV-1 enzyme called reverse transcriptase (RT) is used for this purpose. We have discovered that another HIV-1 protein called Tat is also required for the efficient conversion of HIV-1 RNA into HIV-1 DNA. If HIV-1 lacks Tat, then this tra ....HIV-1 is the virus that causes AIDS. In order for HIV-1 to grow, the viral genetic material must be converted into a form that is compatible with a human host. Specifically, the HIV-1 genetic material is made of RNA while the human genome is composed of DNA. An HIV-1 enzyme called reverse transcriptase (RT) is used for this purpose. We have discovered that another HIV-1 protein called Tat is also required for the efficient conversion of HIV-1 RNA into HIV-1 DNA. If HIV-1 lacks Tat, then this transformation process is inefficient and HIV-1 is not able to grow. Recently our group made a breakthrough discovery on how Tat works. Tat can directly bind to RT and stimulate the conversion process. This research is aimed at a detailed analysis of Tat and RT interaction. This information is required in order to understand how this interaction can be blocked in order to stop HIV-1 growth. In the long-term, results produced by this research will be required to discover novel drugs to combat HIV-AIDS.Read moreRead less
The balance between cell division and programmed cell death is crucial for normal development, maintenance of homeostasis, and immune system function. Inappropriately regulated cell death contributes to the pathogenesis of a wide variety of human diseases including neurodegenerative disorders, autoimmune syndromes and several forms of cancer. Death receptors such as Fas and TNFR1 are cell-surface sensors that trigger cellular destruction by apoptosis in response to specific extracellular death s ....The balance between cell division and programmed cell death is crucial for normal development, maintenance of homeostasis, and immune system function. Inappropriately regulated cell death contributes to the pathogenesis of a wide variety of human diseases including neurodegenerative disorders, autoimmune syndromes and several forms of cancer. Death receptors such as Fas and TNFR1 are cell-surface sensors that trigger cellular destruction by apoptosis in response to specific extracellular death signals. Recent studies have demonstrated that the mechanisms of signal transduction through Fas and TNFR1 differ significantly, however, they both require the adaptor protein FADD to induce apoptosis. In this study we will elucidate the molecular basis of the interactions between FADD and its binding partners using biochemical and biophysical studies. This research will improve our understanding of death receptor-induced apoptosis and the differences in signalling mechanisms. A detailed knowledge of these aspects of death receptor signalling is of significance because they represent critical regulatory steps that could be useful for targeted interventions.Read moreRead less
LMO2-containing Complexes In Leukemia And Blood Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$803,652.00
Summary
Childhood T-cell leukemias have a poor prognosis for recovery. We are determining, with atomic level precision, how the proteins Lmo2 (also linked to prostate and other cancers) and Tal1, and their binding partners contribute to both normal blood cell development and T-cell leukemia. With this information we are developing reagents that can be used to disrupt disease-causing complexes, and which will lead towards the development of new, specific, therapeutics for leukemias and other cancers.
A Functional Interaction Between Domains Of The Flavivirus NS5 Protein Presents A New Target For Antiviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$502,891.00
Summary
Mosquito-transmitted flaviviruses such as dengue, yellow fever, Japanese encephalitis and West Nile infect hundreds of millions of people and cause debilitating and fatal diseases. Developing anti-viral treatments against these diseases is a high priority. Our strategy is to develop small molecules that can bind to specific sites on viral proteins and prevent the virus from replicating and causing disease.
The Structural Basis Of Ligand-Induced Activation Of The Insulin Receptor
Funder
National Health and Medical Research Council
Funding Amount
$640,825.00
Summary
We aim to understand how insulin binds to and activates its cell-surface receptor. This information has implications for the design of anti-diabetic agents targetted directly to the insulin receptor. Diabetes is a global health problem and is classified by the World Health Organization as an epidemic. The results also have implications for the insulin-like growth factor receptor system and the design of anti-cancer therapeutics directed towards it .
Molecular Mechanisms Of G Protein-Coupled Receptor Cross Talk
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aber ....The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aberrations in the normal function of these G protein-coupled receptors have been implicated in a wide variety of disorders, such as schizophrenia, pain and dementia. To date, most therapeutic approaches to treating these disorders have targeted individual types of G protein-coupled receptors thought to play a role in each disease state, but this has met with mixed success. One of the reasons for this is that each disorder actually involves more than one type of G protein-coupled receptor communicating with other types in a complex way. Our current proposal specifically focuses on some of the newer mechanisms that have been suggested to play an important role in the communication between different types of G protein-coupled receptors located in the same type of cell. An understanding of how such receptor proteins can communicate with one another in this situation is absolutely vital in unravelling processes involved in the maintenance of health, abnormalities that lead to disease and in the development of more effective treatments.Read moreRead less
We propose to study the poorly understood, disease-associated process of amyloid formation, using a sensitive and reproducible model developed in our laboratory. Amyloid deposits are a feature of several neurodegenerative and metabolic disorders such as Alzheimer's and Parkinson's disease and are also common in atherosclerotic plaque or atheroma. They are composed of tangled networks of fibrillar proteins together with several non-fibrillar proteins and proteoglycans. Atherosclerotic plaques typ ....We propose to study the poorly understood, disease-associated process of amyloid formation, using a sensitive and reproducible model developed in our laboratory. Amyloid deposits are a feature of several neurodegenerative and metabolic disorders such as Alzheimer's and Parkinson's disease and are also common in atherosclerotic plaque or atheroma. They are composed of tangled networks of fibrillar proteins together with several non-fibrillar proteins and proteoglycans. Atherosclerotic plaques typically consist of fibrous proteins, lipids and foam cells derived from macrophages via receptor-mediated uptake of oxidized low density lipoproteins. Our model system is based on the formation of amyloid fibrils from apolipoprotein (apo) C-II which accumulates in atherosclerotic plaques where it co-localizes with serum amyloid P component, a marker of amyloid fibrils. ApoC-II is a component of plasma lipoproteins and an important activator of the enzyme lipoprotein lipase, which functions in the transport and distribution of triacylglycerols to tissues. We have shown that apoC-II (79 amino acids) readily forms amyloid fibrils under lipid-free conditions, adopting a cross-beta sheet structure that reacts with the amyloid stains thioflavin T and Congo Red. The formation and properties of apoC-II amyloid fibrils and the amyloid-like properties of oxidized lipoproteins are the subject of the present proposal. We will characterize the effects of lipids and oxidation on the rate of formation and the properties of apoC-II amyloid fibrils. We will also study the effects of oxidation on the amyloid-like properties of lipoproteins and their interactions with serum amyloid P component and cell surface receptors.Read moreRead less