Targeting To Mitochondria Of Tail-Anchored Proteins. Defining The Molecular Apparatus Of Targeting.
Funder
National Health and Medical Research Council
Funding Amount
$254,751.00
Summary
The cells of the body have an intricate and dynamic internal architecture, with the components (proteins, lipids, and nucleic acids) of the cell carefully arranged. It is widely viewed that just how each component finds its place in the cell, the cellular adressing system, is of critical importance. This was recognized this year by the award of the Nobel Prize in Medicine to Dr. Gunter Blobel for his work on the signals that direct different proteins to their correct destination. One such destin ....The cells of the body have an intricate and dynamic internal architecture, with the components (proteins, lipids, and nucleic acids) of the cell carefully arranged. It is widely viewed that just how each component finds its place in the cell, the cellular adressing system, is of critical importance. This was recognized this year by the award of the Nobel Prize in Medicine to Dr. Gunter Blobel for his work on the signals that direct different proteins to their correct destination. One such destination is the mitochnondria, the particles in the cell that produce chemical energy. The work in this proposal is designed to define precisely the molecular apparatus that targets a group of proteins to mitochondria. This group, proteins that are inserted into the mitochondria at one end of the protein, includes a variety of critical proteins, including those that determine the life or death of a cell. We will define both the address contained within those proteins, and the machinery on the mitochondria that recognizes that address, and ensures that those proteins will become part of the mitochondria. This research has two applications. By understanding the address, we will be able to decode the vast amount genomic data that is being produced, to predict exactly which proteins are delivered to mitochondria. Secondly, by understanding the targeting machinery, we may begin to design molecules that can inhibit its function, and thus manipulate the delivery of those proteins that affect cell life and death.Read moreRead less
Targeting Of The APC Tumour Suppressor To Mitochondria: Implications For APC Regulation And Cellular Function
Funder
National Health and Medical Research Council
Funding Amount
$390,116.00
Summary
Inherited mutations in the APC gene cause colon cancer, and kills 4,700 Australians every year. About 1 in 21 Australians develop colorectal cancer by the age of 75. APC mutations change cells in different ways, triggering the cancer process. We have discovered a new pathway, involving altered movement of APC to mitochondria in tumour cells. This study will investigate how this cancerous change may help our understanding of colon cancer progression.
Identification of Proteins that Regulate Apoptosis Through Interaction With IAPS. Apoptosis is the process by which multicellular organisms eliminate unwanted cells. Identifying proteins involved in cell death regulation is central to our understanding of disease states arising from aberrations in this process. The mammalian protein DIABLO, promotes cell death by interacting with and antagonising inhibitor of apoptosis proteins (IAPS). Given the existence of several IAP regulatory proteins (IRPs ....Identification of Proteins that Regulate Apoptosis Through Interaction With IAPS. Apoptosis is the process by which multicellular organisms eliminate unwanted cells. Identifying proteins involved in cell death regulation is central to our understanding of disease states arising from aberrations in this process. The mammalian protein DIABLO, promotes cell death by interacting with and antagonising inhibitor of apoptosis proteins (IAPS). Given the existence of several IAP regulatory proteins (IRPs) in insects, other mammalian IRPs probably also exist. These may be of equal importance in regulating apoptosis, especially in tissues where DIABLO is not expressed. The main aim of the proposed study is to idenitify and characterise other IRPs in mammalian cells.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0226463
Funder
Australian Research Council
Funding Amount
$160,000.00
Summary
Fluorescence Lifetime Imaging Facility. The aim of this proposal is to establish the first fluorescence lifetime imaging facility (FLIM) in Australia. The imaging technique provided by the new facility when combined with the use of novel fluorescent protein technology will enable many different events, represented by protein-protein interactions, to be non-invasively, visualised spatially and temporally inside the living cell. The new facility will provide timely state-of -the-art infrastructu ....Fluorescence Lifetime Imaging Facility. The aim of this proposal is to establish the first fluorescence lifetime imaging facility (FLIM) in Australia. The imaging technique provided by the new facility when combined with the use of novel fluorescent protein technology will enable many different events, represented by protein-protein interactions, to be non-invasively, visualised spatially and temporally inside the living cell. The new facility will provide timely state-of -the-art infrastructure necessary for research groups to further develop and maintain their international reputations, will build stronger research collaborations between partner institutions and will attract researchers from overseas.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
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
The role of heparan sulfate proteoglycans in the control of osteoblast phenotype. Very little is known about how bone cells progress from a naive precursor state, through differentiation and then maturation into adult cells. We wish to purify sugars from the bone cell membrane, extracellular matrix and culture medium, and examine the cellular response following the addition of these various sugar fractions to osteoblast cell cultures in combination with known growth factors. If we can control ....The role of heparan sulfate proteoglycans in the control of osteoblast phenotype. Very little is known about how bone cells progress from a naive precursor state, through differentiation and then maturation into adult cells. We wish to purify sugars from the bone cell membrane, extracellular matrix and culture medium, and examine the cellular response following the addition of these various sugar fractions to osteoblast cell cultures in combination with known growth factors. If we can control the progression of osteoblastic cells through the phases of recruitment, proliferation, differentiation and maturation by the addition of specific sugar fractions then we can potentially control bone formation.Read moreRead less
NUCLEAR AND TRANSGOLGI TARGETING AND MEMBRANE INDUCTION BY DENGUE NS5 RNA-DEPENDENT RNA POLYMERASE INTERDOMAIN REGION
Funder
National Health and Medical Research Council
Funding Amount
$450,750.00
Summary
Dengue virus is the causative agent of a mosquito-borne disease, Dengue fever, relevant to northern Queensland, where antibodies from a previous infection can complex with virus of a different serotype in a subsequent infection, and cause a severe, potentially fatal form of the disease (Dengue haemorrhagic fever-Dengue shock syndrome). The present proposal seeks to further understanding of the role of the dengue RNA-dependent RNA polymerase NS5, which is essential for viral RNA replication, with ....Dengue virus is the causative agent of a mosquito-borne disease, Dengue fever, relevant to northern Queensland, where antibodies from a previous infection can complex with virus of a different serotype in a subsequent infection, and cause a severe, potentially fatal form of the disease (Dengue haemorrhagic fever-Dengue shock syndrome). The present proposal seeks to further understanding of the role of the dengue RNA-dependent RNA polymerase NS5, which is essential for viral RNA replication, within the viral infectious cycle. We intend to examine the subcellular targeting properties of a short central region (the interdomain) of NS5, which appears to play multiple roles in targeting to both the perinuclear Golgi-membranes and to the nucleus, as well as in inducing intracellular membranes derived from the Golgi which are the site of viral replication. We will determine how NS5 localisation-membrane induction may differ in insect and primate cells, and attempt to isolate binding partners of NS5 from the nucleus and Golgi compartment of insect and primate cells using various different approaches. Our studies should assist in understanding NS5's critical role in the Dengue infectious cycle, and contribute towards devising new anti-viral strategies such as vaccination and-or therapies targeted at the NS5 interdomain.Read moreRead less