Role Of The Growth Hormone Binding Protein As A Transcriptional Activator
Funder
National Health and Medical Research Council
Funding Amount
$387,226.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This proposal examines a novel way that GH could work, that is by sending the extracellular part of its receptor (GHBP) to the nucleus, wh ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This proposal examines a novel way that GH could work, that is by sending the extracellular part of its receptor (GHBP) to the nucleus, where it can directly activate gene readout. This would have the effect of augmenting the normal action of GH to regulate gene readout. We have exciting preliminary data which makes us think this may be a new mechanism for hormone activation of genes. The level of GHBP in the nucleus is regulated, and if a defect in export of the GHBP occurred, this would lead to accumulation of nuclear GHBP and stimulate cell proliferation. This may be important in cancer cell proliferation, since we find nuclear GHBP in cancers.Read moreRead less
Enhanced Nuclear Transport In Transformed Cells; Implications For Cancer Treatment
Funder
National Health and Medical Research Council
Funding Amount
$628,650.00
Summary
We have found that cancer cells are different to normal cells in terms of their ability to accumulate molecules in the cell nucleus. We intend to pursue this observation in detail, to understand the mechanism thereof, and the extent to which all types of cancer cells are similar in this regard. The results will have high relevance to understanding of oncogenesis, and of utility in approaches to anti-cancer therapies relying on the delivery of nuclear acting drugs.
Structural Basis Of Substrate Recognition By The Membrane-Associated E3 Ubiquitin Ligases
Funder
National Health and Medical Research Council
Funding Amount
$415,244.00
Summary
Membrane-associated E3 ubiquitin ligases control cellular levels of important immunoregulatory molecules and occur in both host- and virus-encoded forms. Target selectivity maps to the transmembrane domains of ligases and their substrates in a little-studied mode of intramembrane molecular recognition. Our goal is to determine the physical basis of this interaction by establishing which sequences drive the association and providing atomic-resolution structures of the membrane-embedded complexes.
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
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
Control of the use of DNA, gene expression, is vital to all living organisms, especially in development and disease. The information in the genes is transferred to an intermediate molecule, mRNA, in a process called transcription. The genetic information in the mRNA is subsequently used, in the process called translation, to make the protein encoded by the original gene. The switching on and off of DNA appears to be most frequently controlled at the transcription step but recently it has become ....Control of the use of DNA, gene expression, is vital to all living organisms, especially in development and disease. The information in the genes is transferred to an intermediate molecule, mRNA, in a process called transcription. The genetic information in the mRNA is subsequently used, in the process called translation, to make the protein encoded by the original gene. The switching on and off of DNA appears to be most frequently controlled at the transcription step but recently it has become apparent that there are many post-transcriptional events that govern how efficiently the genetic information is ultimately converted to protein molecules. In this project we will investigate the molecular mechanisms of several proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs), that appear to play regulatory roles in many of these steps. These proteins appear to affect the longevity and replication of cells, the important chemical changes that take place in RNA after it is transcribed and before it is translated, the movement of the modifed RNAs through the cell and the efficiency of translation. Because of these central functions they are involved in development of tissues such as the brain, and in diseases including lung, skin and brain cancers, and rheumatoid arthritis. In this project we will focus on two RNA molecules, one vital for myelination in the central nervous system and the other for memory.Read moreRead less
Heterogeneous Nuclear Ribonucleoprotein A2-dependent MRNA Trafficking In The Cytoplasm Of Cells.
Funder
National Health and Medical Research Council
Funding Amount
$346,650.00
Summary
Control of the use of DNA, gene expression, is vital to all living organisms, especially in development and disease. The information in the genes of DNA is transferred to an intermediate molecule, mRNA, in a process called transcription. The genetic information in the mRNA is subsequently used to make the protein encoded by the original gene. The switching on and off of DNA appears to be most frequently controlled at the transcription step but recently it has become apparent that there are many ....Control of the use of DNA, gene expression, is vital to all living organisms, especially in development and disease. The information in the genes of DNA is transferred to an intermediate molecule, mRNA, in a process called transcription. The genetic information in the mRNA is subsequently used to make the protein encoded by the original gene. The switching on and off of DNA appears to be most frequently controlled at the transcription step but recently it has become apparent that there are many post-transcriptional events that govern how efficiently the genetic information is ultimately converted to protein molecules. The RNA molecules may be confined to a small region of the cell, resulting in the localization of the protein produced from it; the RNA may be rapidly degraded or stabilized; and the efficiency of production of the protein from its RNA precursor may be modulated by other molecules. It had previously been shown that the mRNA encoding a protein that is an essential structural component of central nervous system myelin is selectively transported to the regions in the cell where the myelin is made. We have identified the molecule that recognises this RNA as a protein called hnRNP A2 and shown how it selects the RNA molecules that have to be transported from the myriad of RNA moleclues in the cell at any given time. hnRNP A2 was previously thought to be confined to the nuclei of cells, but we have shown that it is also present outside the nucleus and is involved in RNA transport in a variety of cell types. hnRNP A2 appears to be directly involved in rheumatoid arthritis, lung cancer and other cancers. It has been proposed as a diagnostic test for cancer as elevated intracellular levels and circulating antibodies against this protein appear before the cancerous cells are visible under the microscope. The major aim of the proposed project is to explore the molecular mechanism by which hnRNP A2 transports RNA molecules in cells.Read moreRead less
Structural domains of beta-tubulin and their role in microtubule dynamics and transport. This study aims to obtain a fundamental understanding of how the structural domains of the cytoskeletal protein beta-tubulin are involved in microtubule structures during cell division and vesicular transport. Using gene-editing technology and coupling this with cell biological approaches and high-resolution cell imaging will enable detailed analysis of the role of beta-tubulin domains in these important cel ....Structural domains of beta-tubulin and their role in microtubule dynamics and transport. This study aims to obtain a fundamental understanding of how the structural domains of the cytoskeletal protein beta-tubulin are involved in microtubule structures during cell division and vesicular transport. Using gene-editing technology and coupling this with cell biological approaches and high-resolution cell imaging will enable detailed analysis of the role of beta-tubulin domains in these important cellular processes. The outcomes will include fundamental new knowledge in cell biology and lead to the development of unique biological models that can be used to understand disease.Read moreRead less
We have generated mice with symptoms mirroring the inflammatory bowel disease, ulcerative colitis (UC). These mice have mutations in the gene producing the major component of the protective mucus layer in the intestine. The mutations lead to a phenomenon known as ER stress. We have shown that ER stress also occurs in UC, opening up a new understanding of this disease. The proposed research will explore links between ER stress and inflammation and test potential new treatments for UC.