Controlling the concentration of calcium inside cells is extremely important for normal cell function. For example, a brief increase in calcium concentration inside muscle cells is essential for muscle contraction and the normal heart beat. This calcium is kept stored in sacs inside cells and is rapidly released when needed through calcium channels known as ryanodine receptors. We have discovered that some proteins (glutathione transferases and intracellular chloride channel proteins) inside cel ....Controlling the concentration of calcium inside cells is extremely important for normal cell function. For example, a brief increase in calcium concentration inside muscle cells is essential for muscle contraction and the normal heart beat. This calcium is kept stored in sacs inside cells and is rapidly released when needed through calcium channels known as ryanodine receptors. We have discovered that some proteins (glutathione transferases and intracellular chloride channel proteins) inside cells can affect how much calcium flows through these calcium channels. The proteins were thought to have other functions and our discovery of their effect on ryanodine receptor calcium channels has caused considerable excitement. We now plan to explore how they do this. We will mutate specific regions of the proteins to discover which regions are important and which are not. We will also look at whether closely related proteins have similar effects. The new class of ion channel modulator that we are studying has the capacity to alter not only respiration, movement and cardiac contraction, but also other aspects cardiovascular function, neuronal activity and immune responses. Understanding the way in which soluble proteins can interact with ion channels may reveal a novel target for drugs that affect ryanodine receptor calcium channel function and allow the rational design of specific drugs to regulate ion channels or ion channel modulators.Read moreRead less
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
Modulating Heat Shock Protein Expression In Skeletal Muscle To Improve The Pathophysiology Of Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$502,361.00
Summary
Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy. Dystrophic muscles are fragile, prone to injury, and regenerate poorly after damage. Defective calcium handling has been implicated in these processes. We have revealed that upregulating levels of stress proteins called _heat shock proteins� (HSPs) can improve calcium regulation in muscular dystrophy. Modulating the HSP response has significant potential to delay the onset or slow the progression of DMD.
RNA Binding Protein Musashi: Role In Folliculogenesis And Oocyte Development
Funder
National Health and Medical Research Council
Funding Amount
$419,223.00
Summary
Women in Australian have opted for social and economic reasons to delay both marriage and childbirth. Both infertility and congenital abnormality is associated with advancing maternal age as the ovarian pool of oocytes declines in number and quality. In this project we aim to gain an understanding of the molecular mechanisms underpinning healthy oocyte development. Insights gained have the potential to alleviate miscarriage, infertility and congenital abnormalities in Australian families.
Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel wh ....Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the immune system. These channels are unusual in that they can move between two states: a soluble state and a state that resides in the cell membrane. We have determined the first structures of this class of channel in both the soluble state and what is believed to be the membrane docking state. This has given us the first atomic picture of how this channel protein can alter its structure so as to carry out its function. In this project, we will determine: how the protein completes the transition into the membrane state; the structures of other key members of this class of channel protein; complexes between channel proteins and other cellular proteins; and the structure of the protein in the membrane state. We will also determine how several drugs control the activity of this channel. The results of our work will have specific implications for our channel and will serve as a paradigm other members of this new class of chloride channel. Understanding how this channel functions and how the current drugs control it will lead to the development of a new class of therapeutic agents that will control these channels by preventing the transition from the soluble to the membrane state.Read moreRead less
Mitochondrial Ribosomal Pentatricopeptide Domain Proteins Regulate Protein Synthesis In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$444,108.00
Summary
Mitochondria in our cells regulate energy production from food and play an important role in health and disease. Defects in mitochondrial protein synthesis lead to severe neurodegenerative and sensory diseases and may contribute to cancer and ageing. This research aims to investigate the role of mitochondrial proteins that regulate translation in mitochondrial diseases. Characterisation of these proteins provides an unexplored resource of potential disease modulators and drug targets.
Structural Determinants Of Siah Ubiquitin Ligase Complexes
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
Controlled degradation of cellular proteins is an important process. The turnover of proteins is a fine balance between protein expression and degradation and alterations can control many cellular processes such as mitosis and intracellular signaling. Whilst a lot of research has been directed at understanding protein expression in response to stimuli such as hormones, stress etc. little has been known about the mechanisms for targeting protein degradation. In recent years it has been shown that ....Controlled degradation of cellular proteins is an important process. The turnover of proteins is a fine balance between protein expression and degradation and alterations can control many cellular processes such as mitosis and intracellular signaling. Whilst a lot of research has been directed at understanding protein expression in response to stimuli such as hormones, stress etc. little has been known about the mechanisms for targeting protein degradation. In recent years it has been shown that proteins can be modified by the addition of a signaling protein called ubiquitin, and it is this modified form that is recognised for degradation. The degradation of these proteins occurs within a large protein complex called the proteasome, which recognizes the ubiquitinated protein substrates. The ubiquitination of proteins is a multistep process, the final step of which is catalyzed by a ubiquitin ligase, or E3 enzyme. It is the E3 which is able to recognize the protein to be degraded, and catalyze the transfer of ubiquitin onto that protein. The E3 proteins (or sometimes complexes) are a diverse group which have to recognize many different proteins, in order that they be degraded at appropriate times. We have been working on the protein Siah (seven in absentia homologue), a member of an E3 complex and important in controlled cell death, cell division and inflammatory responses. One part of the Siah protein is involved in binding proteins and targeting them for ubiquitination, though it is not known how Siah recognizes its targets. Using protein crystallography we have solved the 3D structure of this part of Siah and now propose to co-crystallize Siah with target proteins and binding partners so as to understand how Siah recognizes these proteins. Understanding the basis of these interactions will allow us to determine other potential targets for the Siah protein and also how we may be able to interfere with these interactions with therapeutic drugs.Read moreRead less