Investigating CRAC Channel Assembly And Interactions Important In Immunity
Funder
National Health and Medical Research Council
Funding Amount
$398,247.00
Summary
#ERROR: -Transmission and amplification of signals between subcellular compartments underpins cell function. Calcium ions are cellular messengers that can cross Membranes using specialised pores. CRAC Calcium channels in particular are critical for immune system function,and partner Proteins switch them on and off in a feedback response to compartmental Calcium levels. the objective of my research is to investigate how opening and closing of the CRAC pore is triggered at a molecular level.
Bivalent Analgesics: Rational Design Of Selective Ion Channel Inhibitors With Optimised Mechanism Of Action
Funder
National Health and Medical Research Council
Funding Amount
$904,890.00
Summary
The so-called 'opioid crisis' leading to the death of millions of people worldwide has highlighted the urgent need for development of novel safe and efficacious pain killers without addictive potential. This proposal aims to rationally design novel analgesic compounds by linking different classes of ion channel modulators with desirable properties.
Understanding Uterine Contractility: What Can We Learn From Obesity?
Funder
National Health and Medical Research Council
Funding Amount
$600,792.00
Summary
The incidence of failure to progress in labour has increased in recent years, being linked to the rise in obesity. The result is a significant escalation in the rate of delivery by Caesarean Section (CS) which increases the risk of serious complications during subsequent pregnancies. We have identified five dysfunctional systems associated with poor uterine contraction. We now aim to determine the mechanisms underlying these dysfunctional systems, particularly those mechanisms in common.
Determining Fundamental Mechanisms Compromised In Kir-linked Disease States
Funder
National Health and Medical Research Council
Funding Amount
$600,040.00
Summary
The human nervous system and organs are reliant on precisely controlled transmission of electrical currents through sodium and potassium channels. Their core functions are compromised when currents fail to switch on and off normally. Faulty potassium channels are implicated in diabetes, epilepsy and heart failure. This project re-examines the mechanisms controlling potassium channels, with a view to scientific and therapeutic discrimination between the different classes present in human cells.
Structure-function Studies Of Ion Permeation And Selectivity In Recombinant Glycine Receptor Channels
Funder
National Health and Medical Research Council
Funding Amount
$331,300.00
Summary
Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotr ....Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotransmission underlies a range of inherited neurological diseases and already, it has been shown that the human disorder, familial Startle disease (hyperekplexia) occurs because of point mutations that have impaired the permeation and activation of the glycine receptor (GlyR). Similarly, certain epilepsies are now known to be caused by mutations in, or close to, the channel region in the excitatory acetylcholine receptors (AChRs), which affect channel activation and ion permeation. However, because of their very significant structural and functional similarities, information obtained in one member of the LGIC family of receptors has strong potential application to the other members and the GlyR with its simpler structure has certain advantages for investigation. The first aim of this project is to investigate how the molecular biological structure of these ion channels controls permeation, how it affects how different ions are selectively allowed to move through it and how it affects channel activation. A second related aim is to learn more about the process of desensitization of GlyR receptors, whereby a sustained presence of a high concentration of agonist can cause a reduction in receptor response. A third aim is to specifically investigate the mechanisms underlying the mode of molecular disruption resulting from two new Startle disease mutations, which, in addition to their own inherent clinical value, can also give general information about receptor function.Read moreRead less
Ion Transport In The Malaria Parasite, Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$225,721.00
Summary
Malaria is an infectious disease caused by single-cell protozoan parasites which, during the course of their complex lifecycle, invade the red blood cells of their human hosts. In recent years the emergence and spread of malaria parasites with high levels of antimalarial drug resistance has given rise to the very real possibility that within a few years, there will be large parts of the world in which malaria is an untreatable disease. There is therefore an urgent need for new antimalarial drugs ....Malaria is an infectious disease caused by single-cell protozoan parasites which, during the course of their complex lifecycle, invade the red blood cells of their human hosts. In recent years the emergence and spread of malaria parasites with high levels of antimalarial drug resistance has given rise to the very real possibility that within a few years, there will be large parts of the world in which malaria is an untreatable disease. There is therefore an urgent need for new antimalarial drugs. Despite the enormous clinical significance of the malaria parasite, the basic physiology of this organism is not understood. Pathways involved in ion balance, in the uptake of essential nutrients and in the release of potentially toxic waste products all play a crucial role in the survival of the parasite and are potential chemotherapeutic targets. However the properties of these pathways are, as yet, largely unknown. This work will provide fundamental (and pharmacological) information about these pathways. It will thereby open up exciting new possibilities with regard to the chemotherapy of malaria and will provide a rational basis for a strategy in which these pathways might be exploited as antimalarial drug targets.Read moreRead less
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.