Characterization Of A Novel Family Of LIM-only Proteins; Role In Skeletal Muscle Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$423,564.00
Summary
This project aims to study the role of a new family of related proteins in skeletal muscle. One of these proteins has been shown to be deficient in muscle cancers. These proteins are important for the development and normal functioning of muscle. Related proteins have been shown to be linked with heart failure in animals. These proteins also potentially interact with proteins causing muscular dystrophy. We have identified a new family of proteins in skeletal muscle. These proteins contain so-cal ....This project aims to study the role of a new family of related proteins in skeletal muscle. One of these proteins has been shown to be deficient in muscle cancers. These proteins are important for the development and normal functioning of muscle. Related proteins have been shown to be linked with heart failure in animals. These proteins also potentially interact with proteins causing muscular dystrophy. We have identified a new family of proteins in skeletal muscle. These proteins contain so-called LIM domains, which mediate binding to other proteins. This study proposes to determine how these proteins influence skeletal muscle development and the consequences of abnormal levels of these proteins. This may lead to insights into the mechanism of cardiac failure, muscle cancers and muscular dystrophy.Read moreRead less
Mechanisms Of Action Of The Zinc Finger Protein LMO4 In Breast Oncogenesis
Funder
National Health and Medical Research Council
Funding Amount
$272,859.00
Summary
Breast cancer is the most common cancer to strike Australian women, affecting one in 12 women by age 75. Although treatment of breast cancer has substanially improved over the last few years, approximately 25% of women diagnosed with this cancer will die from the disease. A major objective of cancer research is the identification of genes involved in tumour development and definition of their precise role in both normal and cancer cells. The design of new effective therapeutic inhibitors of canc ....Breast cancer is the most common cancer to strike Australian women, affecting one in 12 women by age 75. Although treatment of breast cancer has substanially improved over the last few years, approximately 25% of women diagnosed with this cancer will die from the disease. A major objective of cancer research is the identification of genes involved in tumour development and definition of their precise role in both normal and cancer cells. The design of new effective therapeutic inhibitors of cancer requires an understanding of the basic molecular and cellular biology behind the genetic changes that contribute to cancer. The focus of our research is to understand normal cellular mechanisms that drive growth and differentiation of breast tissue, and those changes that lead to breast cancer. We are particularly interested in 'master regulators' that are located in the cell nucleus. Nuclear regulators have been implicated in many different types of cancer and leukaemias. We aim to identify the key regulators in breast tissue, characterising both their biological roles and mechanism of action, with the ultimate view of understanding how they divert a normal cell to a cancerous cell. This proposal centres on the characterisation of a specific nuclear regulatory molecule, LMO4, which we have demonstrated to be overexpressed in 56% of human primary breast cancers. Significantly, we have recently shown that overexpression of LMO4 predicts poor outcome in breast cancer patients. We have also shown that this protein interacts with the breast tumour suppressor protein BRCA1, as well as a number of other proteins. These studies will include defining LMO4 s role in governing cell growth in breast cancer cells and that of the proteins that bind to this regulator. We will also assess the role of LMO4 in controlling cell invasion and metastasis of breast cancer cells in mouse models since we have preliminary evidence that it may be a critical regulator of these processes.Read moreRead less
The Role Of The Alveolar Macrophage In The Regulation Of Inflammation And Matrix Destruction In COPD
Funder
National Health and Medical Research Council
Funding Amount
$397,420.00
Summary
Chronic obstructive pulmonary disease (COPD) is a major public health problem world-wide. COPD is a common disease and a leading cause of morbidity and mortality. The prevalence, morbidity and mortality of COPD are increasing in many westernized countries. Chronic cigarette smoking is the main cause of COPD, and the demographics of COPD reflect the demographics of cigarette smoking. Globally, 47% of men and 12% of women smoke, but only 15% of smokers will develop COPD. Cells within the lung call ....Chronic obstructive pulmonary disease (COPD) is a major public health problem world-wide. COPD is a common disease and a leading cause of morbidity and mortality. The prevalence, morbidity and mortality of COPD are increasing in many westernized countries. Chronic cigarette smoking is the main cause of COPD, and the demographics of COPD reflect the demographics of cigarette smoking. Globally, 47% of men and 12% of women smoke, but only 15% of smokers will develop COPD. Cells within the lung called alveolar macrophage produce substances called proteins called cytokines and matrix metalloproteinases (MMPs) which may be important in the development of emphysema or COPD. In COPD, these patients have an inflammatory and destructive process in their lungs, which leads to a progressive loss of breathing capacity, and ultimately death. There have been significant improvements in the treatment of asthma over the last 30 years. Effective new drugs such as selective and long-acting bronchodilators, more effective inhaled corticosteroids, and improved delivery systems have been introduced. Arguably inhaled steroids may be the single most important treatment in preventing the symptoms and exacerbations of asthma and although useful in asthma, the benefits of inhaled steroids in COPD has not yet been established, but inhaled steroids are still used in the treatment of COPD despite the paucity of evidence for its usefulness in patients with COPD. This treatment is expensive and may also produce side-effects. We would like to investigate the effect of inhaled steroids on several inflammatory and destructive processes in patients with COPD. These studies will form the basis of a more rational approach in the management of COPD. Improved understanding of the molecular mechanisms that underlie COPD could lead to improved treatments for this disease which is set to be the third most important cause of death in 2010.Read moreRead less
In Vivo Role Of LMO4 And Isolation Of An LMO4-containing Proteosome In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
Breast cancer is the most common cancer to affect women, with one in 10 developing the disease. Although treatment of breast cancer has substantially improved over the last few years, 25% of women diagnosed with this cancer will die from the disease. A major objective of cancer research is the identification of genes involved in tumour development and definition of their precise role in both normal and cancer cells. The design of effective therapeutic inhibitors of cancer requires an understandi ....Breast cancer is the most common cancer to affect women, with one in 10 developing the disease. Although treatment of breast cancer has substantially improved over the last few years, 25% of women diagnosed with this cancer will die from the disease. A major objective of cancer research is the identification of genes involved in tumour development and definition of their precise role in both normal and cancer cells. The design of effective therapeutic inhibitors of cancer requires an understanding of the basic molecular and cellular biology behind the genetic changes thought to contribute to cancer. The focus of our research is to understand normal cellular mechanisms that drive growth and differentiation of breast tissue, and those changes that lead to breast cancer. Nuclear regulatory proteins have been implicated in many different types of cancers and leukaemias. We aim to identify the key regulators in breast tissue, characterising both their structural properties and biological roles, with the ultimate view of understanding how they divert a normal cell to a cancerous cell. This proposal centres on the characterisation of a specific regulatory molecule which we recently demonstrated to be overexpressed in 56% of human primary breast cancers and in 38% of pre-invasive ductal carcinoma in situ. These studies will include defining its normal biologic function and identification of the proteins that this regulator associates with in breast cancer cells.Read moreRead less
QacA-mediated Multidrug Resistance And Export In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph) which are resistant to almost all available anti-staphylococcal agents are responsible for serious infections among hospitalised patients; in some hospitals such outbreaks reach epidemic proportions. In these bacteria, resistance has emerged to all classes of antimicrobial agents, including antibiotics and antiseptics-disinfectants commonly used in the hospital environment, largely due to the acquisition of resistance deter ....Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph) which are resistant to almost all available anti-staphylococcal agents are responsible for serious infections among hospitalised patients; in some hospitals such outbreaks reach epidemic proportions. In these bacteria, resistance has emerged to all classes of antimicrobial agents, including antibiotics and antiseptics-disinfectants commonly used in the hospital environment, largely due to the acquisition of resistance determinants. These determinants encode for proteins which provide the bacterial cell with a range of different biochemical mechanisms to evade antibiotic chemotherapy. Specifically, this project seeks to increase our understanding of proteins which confer resistance by pumping a variety of structurally-dissimilar antimicrobials out of the bacterial cell. Proteins which recognise such a broad spectrum of compounds are called multidrug resistance proteins and present a disturbing clinical threat since the acquisition of one such system by a cell may simultaneously decrease its susceptibility to a number of antimicrobials. Similar multidrug pumps are widespread in nature and are credited for resistance to antibiotics and other chemotherapeutic drugs in many pathogenic organisms, such as the bacteria responsible for tuberculosis, and in human cancer cells. In this project, we aim to characterise the QacA multidrug resistance protein which is involved in pumping many different antimicrobial compounds from staphylococcal cells. We will identify the regions of the QacA multidrug resistance protein which bind the compounds and examine how the protein expels them to give resistance. These studies are a prerequisite for the design of more effective antibacterial compounds able to bypass or block these drug resistance pumps, and will also provide fundamental knowledge applicable to the problem of multidrug resistance in other infectious diseases and cancer.Read moreRead less
Structural Determinants Of Siah Ubiquitin Ligase Complexes
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
Controlled degradation of cellular proteins is an important process. The turnover of proteins is a fine balance between protein expression and degradation and alterations can control many cellular processes such as mitosis and intracellular signaling. Whilst a lot of research has been directed at understanding protein expression in response to stimuli such as hormones, stress etc. little has been known about the mechanisms for targeting protein degradation. In recent years it has been shown that ....Controlled degradation of cellular proteins is an important process. The turnover of proteins is a fine balance between protein expression and degradation and alterations can control many cellular processes such as mitosis and intracellular signaling. Whilst a lot of research has been directed at understanding protein expression in response to stimuli such as hormones, stress etc. little has been known about the mechanisms for targeting protein degradation. In recent years it has been shown that proteins can be modified by the addition of a signaling protein called ubiquitin, and it is this modified form that is recognised for degradation. The degradation of these proteins occurs within a large protein complex called the proteasome, which recognizes the ubiquitinated protein substrates. The ubiquitination of proteins is a multistep process, the final step of which is catalyzed by a ubiquitin ligase, or E3 enzyme. It is the E3 which is able to recognize the protein to be degraded, and catalyze the transfer of ubiquitin onto that protein. The E3 proteins (or sometimes complexes) are a diverse group which have to recognize many different proteins, in order that they be degraded at appropriate times. We have been working on the protein Siah (seven in absentia homologue), a member of an E3 complex and important in controlled cell death, cell division and inflammatory responses. One part of the Siah protein is involved in binding proteins and targeting them for ubiquitination, though it is not known how Siah recognizes its targets. Using protein crystallography we have solved the 3D structure of this part of Siah and now propose to co-crystallize Siah with target proteins and binding partners so as to understand how Siah recognizes these proteins. Understanding the basis of these interactions will allow us to determine other potential targets for the Siah protein and also how we may be able to interfere with these interactions with therapeutic drugs.Read moreRead less
Characterisation Of The Growth Receptor Bound 7 (Grb7) Protein And Protein And RNA Partners Involved In The Regulation Of Stress Granule Formation And Cell Migration.
Funder
National Health and Medical Research Council
Funding Amount
$643,958.00
Summary
This proposal is to investigate the Grb7 protein that occurs at very high levels in some types of cancer cells, including breast cancer cells. It is thought that Grb7 contributes to the progression of cancer by directly affecting the regulation of other genes. We will investigate the way in which this protein interacts with other proteins and RNA that could underlie the cancer growth and spread. A better understanding of the Grb7 protein will help to establish its potential as a novel drug targe ....This proposal is to investigate the Grb7 protein that occurs at very high levels in some types of cancer cells, including breast cancer cells. It is thought that Grb7 contributes to the progression of cancer by directly affecting the regulation of other genes. We will investigate the way in which this protein interacts with other proteins and RNA that could underlie the cancer growth and spread. A better understanding of the Grb7 protein will help to establish its potential as a novel drug target.Read moreRead less