Regulation Of Pre-mRNA And MRNA Processing By The Neuron-specific Hu RNA-binding Proteins
Funder
National Health and Medical Research Council
Funding Amount
$477,750.00
Summary
The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, t ....The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, this activation is just the start of the process to produce an active protein. In higher organisms, these RNA copies almost always contain interruptions called introns, which must be excised from the RNA. Also, protein factors bound to specific RNAs can dictate whether the RNA is used to make protein or not, and these factors can also affect the localisation of the RNA to a specific sub-cellular destination, giving rise to highly localised protein expression. Evidence suggests that neurons are a cell type that rely heavily on mechanisms of RNA regulation. During development neurons become highly polarised, acquiring an axon which can elongate and find distant synaptic targets. While much is known about how axon growth cones respond to various guidance cues, the mechanisms by which the axon is able to translate this guidance cue information into structural changes which allow the growth cone to expand or collapse is largely unexplored. Recent evidence suggests that accurate growth cone guidance is absolutely dependent upon local protein synthesis. The functional corollary of this finding is that axon guidance requires RNA localisation and control of protein synthesis of RNAs in the growth cone. This phenomenon of spatial gene regulation within an individual cell is a central research interest for understanding how the brain functions.Read moreRead less
Cytoprotection By Erythropoietin In Hypoxia-ischaemia Of The Kidney And Brain
Funder
National Health and Medical Research Council
Funding Amount
$477,661.00
Summary
We aim to make a significant research impact by describing the complex mechanisms responsible for protecting kidney and brain cells from stress caused by a lack of oxygen. In particular we will establish whether the compound erythropoietin (Epo), which occurs naturally in the human body but its human recombinant form can also be used as a treatment, may be useful in protecting cells from death following a shortage of oxygen. . We have already described how Epo can protect the kidney, but no one ....We aim to make a significant research impact by describing the complex mechanisms responsible for protecting kidney and brain cells from stress caused by a lack of oxygen. In particular we will establish whether the compound erythropoietin (Epo), which occurs naturally in the human body but its human recombinant form can also be used as a treatment, may be useful in protecting cells from death following a shortage of oxygen. . We have already described how Epo can protect the kidney, but no one has yet described its action on kidney cell differentiation or its effect on structural and vascular support in the injured kidney. When might Epo treatment be effective? Could it protect against chronic renal disease? Likewise, whilst more very pre-term babies survive, this is a crucial period when they are at heightened sensitivity to lack of oxygen and they are at risk of brain damage and poor development because of lack of maturation of key structural cells in the brain. The role of Epo in aiding brain cell maturation and on blood vessel formation and function in this faulty development period is not known. Both of these health problems are major issues causing huge costs to society both financial and emotional. Despite the early evidence of a useful role for Epo in human disease treatment, current experimental and clinical data demonstrate the importance of further thorough investigation of mechanisms and cellular pathways that will underpin improvements in clinical outcomes. A particular strength of our project is that by comparing similarities and differences in the kidney and brain, we will be able to elucidate the mechanisms of action of Epo and its analogues.Read moreRead less
Relaxin Signalling In The Endometrium And The Regulation Of Early Pregnancy
Funder
National Health and Medical Research Council
Funding Amount
$466,125.00
Summary
Relaxin is a hormone, that is made in the ovary and the uterus, and plays a very important role in supporting the growth and development of the uterus so that the young embryo can implant properly. In fact, early pregnancy loss is associated with altered levels of relaxin in the blood. Very little is known about how relaxin works in the uterus. This project aims to address this important function, and makes use of cultured uterine cells prepared from tissues taken from women undergoing hysterect ....Relaxin is a hormone, that is made in the ovary and the uterus, and plays a very important role in supporting the growth and development of the uterus so that the young embryo can implant properly. In fact, early pregnancy loss is associated with altered levels of relaxin in the blood. Very little is known about how relaxin works in the uterus. This project aims to address this important function, and makes use of cultured uterine cells prepared from tissues taken from women undergoing hysterectomy for fibroids or similar illnesses. When these cells are grown in culture, we can mimic in vitro many of the events that occur in early pregnancy, causing the cells to differentiate and grow just as they would in vivo. Relaxin appears to exert its important effects on these cells by causing the concentration of the second messenger cAMP in the so-called stromal cells to increase greatly and in a sustained manner. It is this cAMP which is then responsible for many of the changes which are essential for healthy pregnancy. A knowledge of the molecular mechanisms behind these effects would help us firstly to understand how the uterus becomes receptive to an implanting embryo, and may explain why some women lose their babies in early pregnancy, or develop some of the negative symptoms associated with placental development such as growth restriction and preeclampsia. Relaxin appears to stimulate cells through the mediation of a new type of cell surface receptor, called LGR7. Whilst structurally this receptor looks like those for many other hormones, belonging to the group of so-called G-protein coupled receptors, it does not behave like these in natural uterine cells. Instead it appears to make use of completely new signaling pathways inside the cells. This project aims to unravel and understand these new pathways, thus providing information not only of importance for diagnosis and treatment of early pregnancy problems, but also of relevance for all other similar receptors.Read moreRead less
Regulation of DNA replication initiation during Drosophila development. This proposal addresses the fundamental issue of the regulation of DNA
replication during development, using the animal model system, Drosophila melanogaster. This research uses a whole animal genetic and cell biological approach to explore DNA replication regulatory mechanisms that are present in multicellular organisms but not in yeast. The work undertaken here will make a significant contribution to our understanding of ....Regulation of DNA replication initiation during Drosophila development. This proposal addresses the fundamental issue of the regulation of DNA
replication during development, using the animal model system, Drosophila melanogaster. This research uses a whole animal genetic and cell biological approach to explore DNA replication regulatory mechanisms that are present in multicellular organisms but not in yeast. The work undertaken here will make a significant contribution to our understanding of DNA replication regulation within a developing organism that will be relevant to all animals.Read moreRead less
Unveiling and characterisation of a fundamental pathway important in cell division. This work will have a major impact by producing top quality research that addresses a fundamental biological question of relevance to all organisms. The research will advance understanding of genetic factors important in foetal and early childhood development and proliferative disorders that occur during ageing. This work will provide intellectual and practical training to Honours and PhD students and postdoctora ....Unveiling and characterisation of a fundamental pathway important in cell division. This work will have a major impact by producing top quality research that addresses a fundamental biological question of relevance to all organisms. The research will advance understanding of genetic factors important in foetal and early childhood development and proliferative disorders that occur during ageing. This work will provide intellectual and practical training to Honours and PhD students and postdoctoral researchers in the disciplines of Molecular Genetics, Molecular & Cellular Biology, Developmental Cell Biology, Mass Spectrometry and Proteomics, which will be of immense benefit to their scientific careers and the Australian scientific community.Read moreRead less
Constructing an embryo. This project investigates the cellular and molecular mechanisms underlying temporal and spatial organisation in the eutherian preimplantation embryo. It will examine: the relative roles of cell cycle and circadian clocks in developmental timing; the molecular mechanism by which intercellular adhesion patterns influence spatial organisation; the extent to which marsupials use similar timing and spatial localisation mechanisms to eutherians; the impact of in-vitro manipulat ....Constructing an embryo. This project investigates the cellular and molecular mechanisms underlying temporal and spatial organisation in the eutherian preimplantation embryo. It will examine: the relative roles of cell cycle and circadian clocks in developmental timing; the molecular mechanism by which intercellular adhesion patterns influence spatial organisation; the extent to which marsupials use similar timing and spatial localisation mechanisms to eutherians; the impact of in-vitro manipulations over the first 5 days of mouse pregnancy on embryonic temporal and spatial organisation.Read moreRead less