Regulation Of PtdIns(3,4,5)P3 By Inositol Polyphosphate 5-phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5- ....Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5-phosphatases. We propose the 5-phosphatases are essential for normal cell growth. Several studies have suggested in their absence tumour formation may occurr. We have identified a new member of this enzyme family called SHIP-2. This proposal aims to investigate the mechanisms by which this enzyme family metabolises signalling molecules and thereby regulates cell growth. We will also characterize how the 5-phosphatases control the normal pathways by which primitive cells differeniate into mature cells.Read moreRead less
Analysis Of Intracellular Signalling And Biological Activities Of The GM-CSF Receptor Family Using Constitutive Mutants
Funder
National Health and Medical Research Council
Funding Amount
$505,699.00
Summary
The cytokines GM-CSF, IL-3 and IL-5 stimulate the growth and actions of a wide range of blood cells. Each binds to a receptor on the cell surface which then triggers the generation of a number of signals inside the cell; it is these signals that are responsible for the cytokine?s actions. We have previously generated a panel of constitutive mutant forms of the beta subunit which is shared by the GM-CSF, IL-3 and IL-5 receptors. These constitutive mutants trigger signals even in the absence of th ....The cytokines GM-CSF, IL-3 and IL-5 stimulate the growth and actions of a wide range of blood cells. Each binds to a receptor on the cell surface which then triggers the generation of a number of signals inside the cell; it is these signals that are responsible for the cytokine?s actions. We have previously generated a panel of constitutive mutant forms of the beta subunit which is shared by the GM-CSF, IL-3 and IL-5 receptors. These constitutive mutants trigger signals even in the absence of the cytokine; importantly, the different mutants appear to trigger only a subset of the signals generated by the normal receptor. The aim of this project is to use our panel of constitutive beta subunit mutants to determine how the GM-CSF, IL-3 and IL-5 receptors generate signals inside the cell and how these signals lead to the various biological actions of the receptors on blood cell growth and maturation. Findings from this research will be relevant to the understanding and treatment of diseases which involve abnormal growth or function of blood cells such as leukaemia and inflammatory diseases.Read moreRead less
This established team of investigators will research into the molecular control of white blood cell formation and function, using a multidisciplinary, team approach to fundamental biological questions with a focus on potential clinical and commercial outcomes. The team will also attempt to identify new validated targets for therapeutic intervention by using both forward and reverse genetic approaches in mice coupled with complete phenotypic analyses of the blood cell system.
Characterization Of Novel Regulators Of Erythropoiesis
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature fu ....Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature functional cells. We have identified six molecules which interact with Lyn in red blood cells. We have shown that amolecule called HS1 is important for epo function in individual red blood cells and now we plan to investigate its functions in whole animals, including mice that lack the HS1 gene. We have also shown that a molecule called Trip1 is important for red blood cell development. Interestingly, this molecule also interacts with the thyroid hormone receptor and can influence the effects of epo and thyroid hormone on red blood cell development. The interplay between these two hormones will be looked at in more detail both at the cell and whole animal levels in normal mice and those lacking the thyroid hormone receptor gene. The third Lyn binding molecule we isolated is a novel gene-we have named it ankyrin repeat protein in line with the molecules it is related to. This gene is expressed in red blood cells and we aim to investigate what role it plays in the development of these cells. The fourth gene is also novel and is closely related to another called AFAP-110, which can exert effects on the structure of a cell. Its role in red blood cell structure will also be investigated. Finally, the last two molecule we have identified are both novel and are unrelated to any other known proteins. As above, the effects of these two molecules on red blood cell development will be investigated.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0668266
Funder
Australian Research Council
Funding Amount
$264,000.00
Summary
High Resolution Cellular and Molecular Imaging System. Understanding where molecules are within cells, and how they interact with each other, is fundamental to significant advances being made in biology. Our research will use advanced imaging techniques to localize proteins within a variety of cells including neurons and germ cells. We will be able to determine how the different molecules within a single cell interact with each other. This information is relevant to many biological mechanisms ....High Resolution Cellular and Molecular Imaging System. Understanding where molecules are within cells, and how they interact with each other, is fundamental to significant advances being made in biology. Our research will use advanced imaging techniques to localize proteins within a variety of cells including neurons and germ cells. We will be able to determine how the different molecules within a single cell interact with each other. This information is relevant to many biological mechanisms and to many human diseases. Furthermore, our research will help maintain Australia's strong international reputation in the fields of neuroscience, protein trafficking and stem cells. Read moreRead less
A role for Cited2, Transforming Growth Factor-beta and matrix metaloproteinases in trophoblast invasion and placenta formation. The placenta is essential for the growth and development of the fetus, and if it fails to form correctly during pregnancy, it can have dramatic effects that can result death in utero, or adult onset diseases. Our research aims to understand how one protein functions in placenta formation. We will also investigate how this protein works at the molecular level in a proces ....A role for Cited2, Transforming Growth Factor-beta and matrix metaloproteinases in trophoblast invasion and placenta formation. The placenta is essential for the growth and development of the fetus, and if it fails to form correctly during pregnancy, it can have dramatic effects that can result death in utero, or adult onset diseases. Our research aims to understand how one protein functions in placenta formation. We will also investigate how this protein works at the molecular level in a process that enables single cells to respond to molecules sent from a distance by other cells (TGF-beta signalling). This process is also very important for a host of other biological processes relevant to human health, including cancer.Read moreRead less
Gene Discovery and Functional Analysis of Copper Homeostasis Genes in Drosophila. Copper is a vital nutrient required for the formation and maintenance of bones, blood vessels and the central nervous system, but copper is also potentially toxic when in excess. Homeostatic mechanisms are needed to maintain safe levels of copper in the body and disruptions to these mechanisms are associated with disorders such as Alzheimer's disease, heart disease and osteoporosis. We are investigating the regulat ....Gene Discovery and Functional Analysis of Copper Homeostasis Genes in Drosophila. Copper is a vital nutrient required for the formation and maintenance of bones, blood vessels and the central nervous system, but copper is also potentially toxic when in excess. Homeostatic mechanisms are needed to maintain safe levels of copper in the body and disruptions to these mechanisms are associated with disorders such as Alzheimer's disease, heart disease and osteoporosis. We are investigating the regulation of a key copper pump, the Menkes protein, which helps control copper levels in the body and we are using the genetic advantages of the fruit fly Drosophila to discover new genes that regulate Menkes activity and therefore copper levels. These studies could lead to novel therapies for a range of copper-related disorders.Read moreRead less
Defining in molecular terms cis-inhibition as a means to inhibit Notch signaling. Normal development of a baby and our health after birth is dependent on how our cells behave. Signals move between cells and within them to tell them what to do. Proteins interacting with other proteins mostly transmit these signals. This research focuses on a protein named Notch and the signals that it transmits. Notch functions in normal processes, such as blood vessel formation; but abnormal signaling causes and ....Defining in molecular terms cis-inhibition as a means to inhibit Notch signaling. Normal development of a baby and our health after birth is dependent on how our cells behave. Signals move between cells and within them to tell them what to do. Proteins interacting with other proteins mostly transmit these signals. This research focuses on a protein named Notch and the signals that it transmits. Notch functions in normal processes, such as blood vessel formation; but abnormal signaling causes and/or contributes to pathological situations such as degenerative disease and cancer. We are working to understand how the Notch signal is made and how to control it when it is abnormal. This will allow new medications to be developed to help people who have cancer and other Notch-related illnessesRead moreRead less
Socs proteins in development and disease. Socs proteins are a component of a pathway that is central to a range of developmental processes, including embryonic development. In addition, there is evidence that these proteins are perturbed in several disorders. This Project will enhance our understanding of the Socs proteins and their role in disease, and ultimately provide an opportunity to identify new therapeutic strategies.