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
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
Role Of Hsp40 And Hsp70 In Huntingtin Misfolding, Oligomerization And Inclusion Assembly
Funder
National Health and Medical Research Council
Funding Amount
$590,103.00
Summary
Huntington disease results from a mutation that causes the Htt protein to become abnormally sticky and form toxic clusters in neurons. Cells have natural defences to clustering with proteins called chaperones, which are exciting therapeutic targets. This project will examine how chaperones defend against toxic Htt clustering with cutting-edge imaging technologies. The knowledge gained will aid in designing therapeutic strategies that stimulate the defence processes and suppress the clusters.
Developing Novel Molecules That Target Hormone Receptors As An Alternative Cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$459,867.00
Summary
A promising class of cancer drugs target heat shock protein 90 (Hsp90) and prevent Hsp90 from maintaining its ~100 proteins involved in cell growth. However, all current Hsp90 chemotherapeutics non-selectively target proteins maintained by Hsp90, and induce a cell rescue mechanism involving Hsp70. We describe the development of a novel molecule that will selectively control cell growth and prevent cell rescue via a unique Hsp90 regulated mechanism.
Understanding Age-related Protein Aggregation. The Mechanism Of Cataract And Its Prevention
Funder
National Health and Medical Research Council
Funding Amount
$709,333.00
Summary
Cataract arises from clouding of the eye lens due to the aggregation of crystallin proteins whose high concentration and close packing facilitate lens transparency. This proposal will investigate crystallin structure and interactions to understand the reasons for cataract formation and its prevention via the design of aggregation inhibitors. The results will facilitate the development of drugs to prevent cataract and other related protein aggregation diseases, e.g. Alzheimer’s and Parkinson’s.
Directed Molecular Evolution Of G Protein-coupled Receptors For Stable And Functional Expression In Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$383,479.00
Summary
Approximately half of all prescription drugs on the market act on G protein coupled receptors (GPCRs). The mechanisms underlying GPCR function are mainly unknown due to a lack of structural information. No solved structures exist for any of the estimated 800 human GPCRs, making it difficult to design new drugs. By applying advanced protein engineering techniques I aim to produce human GPCRs in bacteria to ultimately acquire structural information, which will enable novel drug development.
Disrupting Mucin-mucin Interactions To Treat Respiratory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$480,531.00
Summary
Diseases like asthma, emphysema and cystic fibrosis all feature the overproduction of mucus in the lungs that make it very difficult for patients to breathe and increases their susceptibility to infections. Few therapies are available for thinning this mucus, which is made thick by a network of linkages between proteins. We are studying these linkages and developing methods to break them up. This research could yield new mucus-thinning drugs to treat lung diseases.
Mechanisms Regulating Mitochondrial Outer Membrane Permeabilisation During Programmed Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$306,562.00
Summary
Apoptosis is a form of cell suicide that is vital in human development and health by removing damaged or unwanted cells in a regulated manner. Disturbances in this pathway are known to be the cause of cancers and other diseases. This research will investigate how the pivotal step in cell death, termed mitochondrial outer membrane permeabilisation (MOMP) is regulated.
Peptide Toxins From Animal Venoms Specifically Targeting Voltage-gated Sodium Channels As Novel Analgesics And Pesticides
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
This project aims to understand how certain animal toxins that cause analgesic and pesticidal effects in model animals interact with biological ion channels in atomistic detail using computational techniques. By understanding the detailed molecular interactions involved in the binding of the toxins to channels, toxin variants with improved potency and specificity may be designed as promising templates for novel analgesics and pesticides.