Regulation Of Hedgehog Signalling Through Intracellular Trafficking Events
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which ....The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which operate to ensure that this complex pathway of interacting molecules functions correctly during embryonic development. By understanding how this regulation occurs we will gain valuable insight into how disruption of this pathway results in such a range of disease, as well as into how agents which modulate this pathway may potentially act in a therapeutic setting.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0454170
Funder
Australian Research Council
Funding Amount
$187,341.00
Summary
Biacore3000-Expansion of Proteomics Facility. The sequencing of the human genome has led to redirection of effort towards the rapid characterisation of the products of genes, proteins. This project will establish state of the art facilities for protein identification and characterisation in the Hunter Region. The investigators are representative of several major research programs and are unified by their specific expertise in the fundamental molecular mechanisms underlying the control of cellula ....Biacore3000-Expansion of Proteomics Facility. The sequencing of the human genome has led to redirection of effort towards the rapid characterisation of the products of genes, proteins. This project will establish state of the art facilities for protein identification and characterisation in the Hunter Region. The investigators are representative of several major research programs and are unified by their specific expertise in the fundamental molecular mechanisms underlying the control of cellular processes in plants, animals and humans. Understanding these mechanisms will provide the basis for improved management of the environment and pathological conditions through identifying molecular targets for diagnosis, genetic manipulation or drug design.Read moreRead less
Molecular control of apoptosis and protein homeostasis. A million cells are produced every second by cell division. At the same time a million cells commit suicide by a process called apoptosis. When cells fail to die when they should they can develop into cancers. In heart attacks, stroke and neurodegenerative diseases, many cells appear to activate their self destruct mechanism to die unnecessarily. Drugs that can cause cancer cells to kill themselves, or drugs that prevent cells dying when th ....Molecular control of apoptosis and protein homeostasis. A million cells are produced every second by cell division. At the same time a million cells commit suicide by a process called apoptosis. When cells fail to die when they should they can develop into cancers. In heart attacks, stroke and neurodegenerative diseases, many cells appear to activate their self destruct mechanism to die unnecessarily. Drugs that can cause cancer cells to kill themselves, or drugs that prevent cells dying when they shouldn't, would make a major impact on many important diseases. Understanding the molecular mechanisms of cell death is the first step towards developing these drugs.Read moreRead less
The mechanisms and roles of receptor clustering in cell activation and wound healing by growth factors. Growth factors regulate cell proliferation, migration and differentation by interaction with receptors. Such receptors are usually localized at the cell surface, and require intracellular transduction systems to transmit the signal to the cell interior. We have recently shown the hormone-induced clustering of heterologous hormone receptors in cells, and that this occurs with the co-clustering ....The mechanisms and roles of receptor clustering in cell activation and wound healing by growth factors. Growth factors regulate cell proliferation, migration and differentation by interaction with receptors. Such receptors are usually localized at the cell surface, and require intracellular transduction systems to transmit the signal to the cell interior. We have recently shown the hormone-induced clustering of heterologous hormone receptors in cells, and that this occurs with the co-clustering of downstream signalling molecules at sites of engagement with the extracellular matrix. In addition, we have found that cells presented with an extracellular matrix respond better to subsequent growth factor stimulation. The project aims to determine the cellular mechanisms underlying receptor clustering and the basis of the receptor-extracellular matrix interaction. This will enhance our understanding of growth factor function in a number of conditions, including wound healing. We will extend our in vitro results to the animal model to define parameters for enhanced wound repair.Read moreRead less
Cellular signals controlling oocyte activation. This research will significantly advance our understanding of the basic biological processes that underpin the fertility rate of all mammals and are key to the immediate and future health and well-being of Australian landscape and society. Understanding the processes that maintain healthy quiescent oocytes over many years before activation and subsequent growth will enable development of methods of increasing productivity in domestic animals and en ....Cellular signals controlling oocyte activation. This research will significantly advance our understanding of the basic biological processes that underpin the fertility rate of all mammals and are key to the immediate and future health and well-being of Australian landscape and society. Understanding the processes that maintain healthy quiescent oocytes over many years before activation and subsequent growth will enable development of methods of increasing productivity in domestic animals and enhancing fertility in endangered species. Knowledge of these cellular mechanisms will underpin biotechnology platforms necessary for novel methods of feral animal population control thus contributing at multiple levels to an economically sustainable Australia.Read moreRead less
Ras Signalling And Cholesterol Efflux From Late Endosomes
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
Accumulation of cholesterol is a hallmark of early atherosclerotic lesions, known as foam cell formation. Hence the stimulation of cholesterol removal (efflux) from macrophages has great therapeutic potential. High Density Lipoproteins (HDL) and apolipoprotein A-I (apoA-I) stimulate efflux via activation of HDL-apoA-I receptors and poorly understood signalling pathways. This application is investigating the role of the Ras-MAPK signalling pathway in promoting efflux from late endosomes.
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0561173
Funder
Australian Research Council
Funding Amount
$207,189.00
Summary
High throughput proteomics - Thermo Finnigan ProteomeX LCQ Integrated Proteomics Workstation. As research in the biological sciences moves into post-genomics era, so attention has focused on the development of technologies capable of characterizing the molecular complexity inherent in the proteome. Recent technical innovations in this field have resulted in the advancement of mass spectrometers that are capable of exemplifying unknown proteins with great efficiency. These new technologies are ....High throughput proteomics - Thermo Finnigan ProteomeX LCQ Integrated Proteomics Workstation. As research in the biological sciences moves into post-genomics era, so attention has focused on the development of technologies capable of characterizing the molecular complexity inherent in the proteome. Recent technical innovations in this field have resulted in the advancement of mass spectrometers that are capable of exemplifying unknown proteins with great efficiency. These new technologies are central to any institution committed to the development of a competitive research nexus in biological sciences. The purpose of this application is to upgrade the mass spectrometry facility at the University of Newcastle such that it is able to provide cutting edge support to the extensive scientific community within the Hunter region.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