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Understanding The Role Of The Putative Phospholipid Translocase ATP11c In B Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$455,153.00
Summary
The immune system protects humans against recurrent infections with a wide range of pathogens. Formation of antibodies is a crucial element of the immune response. Defects in the production of antibodies can lead to recurrent and often life-threatening infections. This project seeks to understand a genetic defect in mice resulting in an almost complete absence of antibody producing cells, thereby causing a disease that is similar to some forms of human immunodeficiency.
Platelets are key blood elements that are essential for the prevention of bleeding in response to injury or infection. Overactive or spontaneously active platelets cause thrombosis and blood clot formation. My laboratory has identified new physiological pathways of activation of platelet metalloproteinases, the enzymes that regulate surface levels of the prothrombotic platelet receptors. By understanding this mechanism of receptor regulation, we can uniquely target platelet receptors in people w ....Platelets are key blood elements that are essential for the prevention of bleeding in response to injury or infection. Overactive or spontaneously active platelets cause thrombosis and blood clot formation. My laboratory has identified new physiological pathways of activation of platelet metalloproteinases, the enzymes that regulate surface levels of the prothrombotic platelet receptors. By understanding this mechanism of receptor regulation, we can uniquely target platelet receptors in people with prothrombotic pathologies.Read moreRead less
The Role Of The Glutamine Transporter SNAT3 In Ion Transport, Cell Signaling And Ammonia Detoxification
Funder
National Health and Medical Research Council
Funding Amount
$393,249.00
Summary
Hepatic encephalopathy is a syndrome observed in patients with liver cirrhosis and is caused by increased amounts of ammonia in the blood. The proposed project investigates a transporter that is involved in ammonia and glutamine metabolism in liver and brain. The two organs are critical to the pathology of liver failure and ammonia toxicity resulting from reduced liver function. The transporter thus could become a drug target for a variety of liver diseases.
A Structural Understanding Of Class B G Protein-coupled Receptor Function
Funder
National Health and Medical Research Council
Funding Amount
$1,289,570.00
Summary
G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins that enable communication from external signals to the inside of cells of the body. Class B GPCRs are a therapeutically important subclass of these receptors and they play crucial roles in bone and energy homeostasis, cardiovascular control and immune response. This grant will uncover fundamental knowledge on how these receptors work, and will enhance future development of therapeutics.
Mechanism Of Activation Of JAK2 By A Class 1 Cytokine Receptor
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Cytokine receptors regulate key processes such as red/white blood cell formation, stature, adiposity and lactation. They use JAK kinases to signal to regulated genes. Here we will use sophisticated technologies able to observe single molecules and crystallography to uncover the mechanism used by these receptors to signal into the cell using a well characterised, simple cytokine receptor, the growth hormone receptor.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE160100097
Funder
Australian Research Council
Funding Amount
$675,000.00
Summary
An Automated Protein Nano-Crystallisation Facility. An automated protein nano-crystallisation facility:
The project aims to establish a high throughput protein nanocrystallisation and imaging facility for protein crystallography. Protein crystallography is an important field of biological research, however there are many proteins, such as integral membrane proteins and transient molecular complexes that are more challenging to crystallise. The facility aims to use state-of-the-art imaging and c ....An Automated Protein Nano-Crystallisation Facility. An automated protein nano-crystallisation facility:
The project aims to establish a high throughput protein nanocrystallisation and imaging facility for protein crystallography. Protein crystallography is an important field of biological research, however there are many proteins, such as integral membrane proteins and transient molecular complexes that are more challenging to crystallise. The facility aims to use state-of-the-art imaging and crystallisation techniques, including second order nonlinear imaging of chiral crystals (SONICC) imaging and lipid cubic phase approaches, to enable structural studies to be undertaken on challenging proteins. This information is often used for the rational development of therapeutics. The facility would support cutting-edge biological research In Australia.Read moreRead less
Structural Determinants Underlying High Conductance GABA-A Channels
Funder
National Health and Medical Research Council
Funding Amount
$364,080.00
Summary
Large proteins called GABA-A receptors distributed widely throughout the brain are responsible for inhibition in most neurons. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics, but these valuable drugs still have unwanted side effects. For example, some of them affect cardiac and respiratory function. There is still a need for new, more effec ....Large proteins called GABA-A receptors distributed widely throughout the brain are responsible for inhibition in most neurons. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics, but these valuable drugs still have unwanted side effects. For example, some of them affect cardiac and respiratory function. There is still a need for new, more effective general anaesthetics. One in every 200 people in Europe and North America suffers from epilepsy and 3% of the population suffers from anxiety. The leading general anaesthetics, anxiolytic and anti-epileptic drugs currently used, act on GABA-A receptors in the brain. The potential annual market for these drugs has been estimated to be US $2.7 billion. The world market for anaesthetics in 1999 was US $1.6 billion. All were discovered by serendipity. If the molecular site and mode of action of these drugs were understood, it is possible that new, more selective drugs could be discovered. The information gained in this project about GABA-A receptors is expected to be useful in understanding how these receptors work and in developing a new generation of drugs acting on GABA-A receptors. In this project we plan to examine what the functional consequences are and how GABA-A receptors colocalise in the membrane, akin to their physical state in the brain. We will examine the effects of drugs on receptors colocalised in the membrane. We have preliminary evidence suggesting that when GABA-A receptors are close to each other they open together so that their inhibitory response is maximised. Drugs are also able to make GABA-A receptors open in concert. The concept that receptors in the membrane talk to each other has been shown to occur for receptors from different classes but we now have evidence that the same type of receptors i.e. GABA-A receptors, are able to talk to each other.Read moreRead less
Molecular Reorganization During K+ Channel Gating: Determination Of Alternate Pore Configurations By X-ray Diffraction.
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Ion channels are specialised pores that control the flow of charge across cell membranes. They have electrical activity, measurable as current. Potassium channels allow only potassium ions to transit the cell membrane to the exclusion of all others. Without potassium channels our nerves, heart, and other organs, would not function. The channels regulate ion flow by an innate ability to open and close at the behest of specific biological signals, and switch easily between physiological states. In ....Ion channels are specialised pores that control the flow of charge across cell membranes. They have electrical activity, measurable as current. Potassium channels allow only potassium ions to transit the cell membrane to the exclusion of all others. Without potassium channels our nerves, heart, and other organs, would not function. The channels regulate ion flow by an innate ability to open and close at the behest of specific biological signals, and switch easily between physiological states. Influencing factors include depolarising pulses and small molecules that bind to their surface, causing the pore to unblock. Hundreds of types of potassium channel, receptive to a variety of cues, exist in man. The architecture of the pore has recently been confirmed, in the form of three-dimensional models of four quite different channels. This has been invaluable in elucidating aspects of ion permeation. It has not, however, satisfactorily explained what causes the pore to open and close, how it does so, and if this mechanism is general to all potassium channels. Complementary models of the same potassium channel would permit a direct comparison of structural features. Only then can one verify the molecular rearrangements accompanying opening. The experimental aim of this project is to acquire such information using X-ray crystallographic methods. An expedient approach is to tackle one of the four channels already crystallised, capturing its alternate configuration. Although this is an ambitious plan, it has the potential to be highly rewarding. It is also of unparalleled scientific interest, if the current level of debate in biophysics circles is anything to go by. A high proportion of the world s pharmaceuticals are directed at ion channels, as numerous diseases have been ascribed to compromised potassium channel activity. Our research outcomes will provide a fresh basis for the rational design of new drug therapies.Read moreRead less
Molecular mechanisms regulating Ca2+ channels formed by Orai and STIM proteins. Store-operated calcium channels play a central role in the functions of all animal cells. They participate in generating the cellular responses to hormones, antigens, growth factors and other physiological stimuli. The aims of this project are to elucidate cellular mechanisms that regulate interaction between the molecular components of store-operated calcium channel, Orai and STIM. Using techniques of electrophysiol ....Molecular mechanisms regulating Ca2+ channels formed by Orai and STIM proteins. Store-operated calcium channels play a central role in the functions of all animal cells. They participate in generating the cellular responses to hormones, antigens, growth factors and other physiological stimuli. The aims of this project are to elucidate cellular mechanisms that regulate interaction between the molecular components of store-operated calcium channel, Orai and STIM. Using techniques of electrophysiology and molecular biology we expect to answer a fundamental question how STIM and Orai proteins interact to form functional store-operated calcium channels, and how the expression of STIM and Orai is regulated.Read moreRead less