Mechanisms of cell death regulation by the Bcl-2 protein family. Through the proposed study, the expected outcome is a better understanding of the important process of how the Bcl-2 family of proteins interact with each to control cell death. Furthermore, as dysfunctional apoptosis signalling contributes to diseases such as autoimmune conditions, neurodegenerative disorders and cancer, a detailed and sound understanding of how the cell death machinery operates should enable the design of more ef ....Mechanisms of cell death regulation by the Bcl-2 protein family. Through the proposed study, the expected outcome is a better understanding of the important process of how the Bcl-2 family of proteins interact with each to control cell death. Furthermore, as dysfunctional apoptosis signalling contributes to diseases such as autoimmune conditions, neurodegenerative disorders and cancer, a detailed and sound understanding of how the cell death machinery operates should enable the design of more effective and importantly, safer therapies against these pathologies.Read moreRead less
Protein degradation in mammals. One mechanism by which the regulation of protein turnover occurs is the balance between the activity of enzymes responsible for the ubiquitination and deubiquitination of target proteins. The majority of targets of this second family of enzymes are unknown. This project proposes a method for the identification of the targets of two specific mammalian deubiquitinating enzymes in order to understand their function and to begin to explore this new research field. ....Protein degradation in mammals. One mechanism by which the regulation of protein turnover occurs is the balance between the activity of enzymes responsible for the ubiquitination and deubiquitination of target proteins. The majority of targets of this second family of enzymes are unknown. This project proposes a method for the identification of the targets of two specific mammalian deubiquitinating enzymes in order to understand their function and to begin to explore this new research field. Knowledge about this new aspect of protein degradation could provide a powerful tool to test the effect of the stabilisation or removal of specific proteins in the cell and also to develop new technologies in protein production.Read moreRead less
Understanding the critical processes that control cell death and using this knowledge to kill cells that have evaded death. Cell death is essential for protecting the body against cancer, and defects in cell death pathways contribute to cancer progression. To design new and better cancer therapies we must understand the critical processes which control cell death, and develop effective ways to either reset, or bypass, defects in cell death pathways that contribute to cancer. The program as outl ....Understanding the critical processes that control cell death and using this knowledge to kill cells that have evaded death. Cell death is essential for protecting the body against cancer, and defects in cell death pathways contribute to cancer progression. To design new and better cancer therapies we must understand the critical processes which control cell death, and develop effective ways to either reset, or bypass, defects in cell death pathways that contribute to cancer. The program as outlined will elucidate the process of mitochondrial outer membrane permeabilization, a critical event in cell death by apoptosis, and determine how to kill cells in which this event is blocked.Read moreRead less
Autophagic vacuole formation in mammalian skeletal muscle; role of FOXO proteins. Loss of muscle tissue is a hallmark of many common health problems including cancer, HIV-Aids and renal failure. Recently, we identified that a family of transcription factors termed the forkhead box class-O (FOXO) winged helix transcription factors are key regulators of both anabolic (building) and catabolic (wasting) signalling pathways. This project will investigate the molecular regulation of cell integrity by ....Autophagic vacuole formation in mammalian skeletal muscle; role of FOXO proteins. Loss of muscle tissue is a hallmark of many common health problems including cancer, HIV-Aids and renal failure. Recently, we identified that a family of transcription factors termed the forkhead box class-O (FOXO) winged helix transcription factors are key regulators of both anabolic (building) and catabolic (wasting) signalling pathways. This project will investigate the molecular regulation of cell integrity by FOXO proteins. Although very basic in nature, these projects will identify how FOXO proteins regulate muscle cell building and wasting and, therefore, present a potential therapeutic target for muscle wasting diseases, making this project highly significant.Read moreRead less
The function of truncated MEK1 protein in a G2 phase cell cycle delay and in mitosis. Understanding cell proliferation. Intracellular signaling pathways controlling cell growth are often mutated in cancers and other hyperproliferative diseases. Understanding precisely how these pathways operate and how mutations of these pathways can contribute to uncontrolled growth can readily provide new targets for preventative therapies or cures. We have identified a novel mechanism regulating one compone ....The function of truncated MEK1 protein in a G2 phase cell cycle delay and in mitosis. Understanding cell proliferation. Intracellular signaling pathways controlling cell growth are often mutated in cancers and other hyperproliferative diseases. Understanding precisely how these pathways operate and how mutations of these pathways can contribute to uncontrolled growth can readily provide new targets for preventative therapies or cures. We have identified a novel mechanism regulating one component of a well studied pathway, the MAPK pathway, and new functions for this component. The contribution of this novel component to mechanisms involved in regulating cell growth previously through to be controlled by the canonical MAPK pathway could change our understanding of the fundamental mechanisms controlling cell growth. Read moreRead less
Function of the unique mitotic form of MEK. Many of the mechanisms controlling normal cell growth and division are known, although there are an increasing number of examples of mechanism having more thn the originally defined functions. We have found that one well studied mechanism, the Ras-Raf-MEK-ERK pathway operates in a unique manner during the phase when cell division occurs, known as mitosis. Understanding this novel mechanism and identifying its function at this critical stage of cell d ....Function of the unique mitotic form of MEK. Many of the mechanisms controlling normal cell growth and division are known, although there are an increasing number of examples of mechanism having more thn the originally defined functions. We have found that one well studied mechanism, the Ras-Raf-MEK-ERK pathway operates in a unique manner during the phase when cell division occurs, known as mitosis. Understanding this novel mechanism and identifying its function at this critical stage of cell division will provide insights into how cell control the partitioning of replicated genome and produce two identical daugther cells.Read moreRead less
Structural investigations into the regulation of programmed cell death. One in three men and one in four women in Australia will develop cancer by the age of 75 at current incidence rates. At its heart, cancer is a disease of uncontrolled cell proliferation. One of the body's main defence mechanisms against excess cell proliferation is Programmed Cell Death, a process which becomes dysfunctional in cancer cells. This work will provide three dimensional images of the machinery that controls Progr ....Structural investigations into the regulation of programmed cell death. One in three men and one in four women in Australia will develop cancer by the age of 75 at current incidence rates. At its heart, cancer is a disease of uncontrolled cell proliferation. One of the body's main defence mechanisms against excess cell proliferation is Programmed Cell Death, a process which becomes dysfunctional in cancer cells. This work will provide three dimensional images of the machinery that controls Programmed Cell Death. This information is critical for the development of drugs designed to re-initiate Programmed Cell Death in cancer cells.Read moreRead less
Insertion and assembly of proteins and lipids into biological membranes. We propose a multi-disciplinary approach to this fundamental biological problem and have established collaborations with experts in the USA, UK and Austria. Benefits from this research program fall into two discrete types. Firstly, detailed knowledge of the mechanism what is now a poorly understood biological process of cellular membrane assembly, with the prospects for using the knowledge for intervention into diseases suc ....Insertion and assembly of proteins and lipids into biological membranes. We propose a multi-disciplinary approach to this fundamental biological problem and have established collaborations with experts in the USA, UK and Austria. Benefits from this research program fall into two discrete types. Firstly, detailed knowledge of the mechanism what is now a poorly understood biological process of cellular membrane assembly, with the prospects for using the knowledge for intervention into diseases such as cancer. Secondly, excellent outcomes are provided for the training of postgraduate students and research staff. This project entails cutting edge technology, and the development of skills not common in Australia.Read moreRead less
Functional characterisation of CMAP, a novel centrosome- and midbody-associated protein. Cell division is a highly regulated process involving many components to produce two daughter cells which contain an equal amount of DNA. Thus incorrect localisation and modification of specific proteins that regulate this process cause cell division errors resulting in genomic instability. We have recently identified a novel protein called CMAP that is involved in the final stages of cell division, which in ....Functional characterisation of CMAP, a novel centrosome- and midbody-associated protein. Cell division is a highly regulated process involving many components to produce two daughter cells which contain an equal amount of DNA. Thus incorrect localisation and modification of specific proteins that regulate this process cause cell division errors resulting in genomic instability. We have recently identified a novel protein called CMAP that is involved in the final stages of cell division, which involves the cleavage of the cell membrane to produce two daughter cells. Here, we aim to characterise the mechanism(s) of CMAP function and to identify and characterise CMAP binding proteins to further understand the mechanisms involved in the final stages of cell division to maintain genomic stability.Read moreRead less
Interactions of Insulin-like Growth Factors and their Binding Proteins with Vitronectin: a structural basis for antagonist design and development. Tissue Therapies Ltd has shown that a patented combination of three biosynthetic molecules, VitroGroR, can promote tissue repair effectively. This project will use biophysical and biochemical techniques to investigate precisely how these molecules interact, and hence provide a rational basis for future developments and improvements of this exciting n ....Interactions of Insulin-like Growth Factors and their Binding Proteins with Vitronectin: a structural basis for antagonist design and development. Tissue Therapies Ltd has shown that a patented combination of three biosynthetic molecules, VitroGroR, can promote tissue repair effectively. This project will use biophysical and biochemical techniques to investigate precisely how these molecules interact, and hence provide a rational basis for future developments and improvements of this exciting new therapeutic strategy.
Conversely, this information would also facilitate the development of antagonists to VitroGroR complexes would provide novel opportunities to treat diseases such as cancer and atherosclerosis that involve excessive production of its component molecules.Read moreRead less