The Structural Basis For Promiscuity Of Drug Binding To HERG K+ Channels
Funder
National Health and Medical Research Council
Funding Amount
$713,035.00
Summary
Special proteins called ion channels control the electrical activity of the heart. Drugs that block ion channels can have the unwanted side-effect of altering the rhythm of the heart beat and causing sudden cardiac death. Extensive efforts are made to screen for this problem during drug development but it is still an inexact science. Here we will use high resolution imaging technologies to get a better understanding of how drugs bind to ion channel proteins.
Identification Of Heterogeneity In Vasodilator Function In Human And Rat Resistance Vessels: Potential Drug Targets?
Funder
National Health and Medical Research Council
Funding Amount
$595,330.00
Summary
The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not w ....The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not well understood. While current drugs for treating vascular disease either reduce vessel constriction or increase dilation, they are not specific for individual arteries; a situation that would allow us to control vascular diseases in a very specific manner. Recently, we have described differences between the ways that individual vessels are controlled. These changes relate to differences in the way that different vessels dilate. AIMS - To further understand normal blood vessel function and the changes that occur in blood vessels in cardiovascular disease, with a focus on the ways that blood vessels dilate in normal states and in obesity-related diseases, such as in hypertension and diabetes. - The eventual aim is to identify the specific ways that arteries function, so that artery-specific drug targets can be identified to treat disease-related changes in cardiovascular disease in a very specific manner. EXPECTED OUTCOMES This project will contribute to understanding blood vessel function in health and disease. The expected eventual outcome is the identification of the mechanisms that underlie the function of different arteries in different parts of the body, so that specific individual vessel function can be targeted to treat vascular disease. Additionally, this work will also verify the relevance of the diet-induced obesity animal model, in terms of the characteristics and causes of human obesity and related cardiovascular disease.Read moreRead less
Discovering the molecular controls of epigenetic inheritance . This project aims to investigate the way in which acquired traits can be inherited. The environment that an individual is exposed to can change the characteristics of not only that individual, but also their children and grandchildren. We do not yet understand the mechanisms by which this “epigenetic inheritance” occurs. Using interdisciplinary approaches, this project combines the power of the model organism Caenorhabditis elegans ....Discovering the molecular controls of epigenetic inheritance . This project aims to investigate the way in which acquired traits can be inherited. The environment that an individual is exposed to can change the characteristics of not only that individual, but also their children and grandchildren. We do not yet understand the mechanisms by which this “epigenetic inheritance” occurs. Using interdisciplinary approaches, this project combines the power of the model organism Caenorhabditis elegans with cutting-edge single molecule microscopy techniques to determine the molecular mechanisms by which the environment can impact future generations. This should ultimately provide society with the means to harness the power of epigenetics.Read moreRead less
Comparing properties of innate immune proteins of bats and humans. Supra-molecular protein complexes known as signalosomes drive our innate immune response by forming large signaling hubs capable of recruiting downstream effectors. This project aims to compare the properties and structure of human and bat signalosomes and discover the molecular origins of the “supra-immunity” of bats. In this context, the project expects to generate new knowledge concerning the fundamental molecular mechanisms t ....Comparing properties of innate immune proteins of bats and humans. Supra-molecular protein complexes known as signalosomes drive our innate immune response by forming large signaling hubs capable of recruiting downstream effectors. This project aims to compare the properties and structure of human and bat signalosomes and discover the molecular origins of the “supra-immunity” of bats. In this context, the project expects to generate new knowledge concerning the fundamental molecular mechanisms that regulate the signalosomes. The intended outcome is to answer the long-standing question of control of speed and amplitude of innate immune response at the molecular level. Both locally and internationally, this new approach should provide benefits across structural biology, molecular evolution and biotechnology.Read moreRead less
In depth characterisation of the gamma delta T cell immune synapse. This project aims to comprehensively characterise the activation principles of gamma delta T cells. These cells have an understudied but central role in vertebrate immunity and development. A missing piece of the puzzle is how gamma delta T cells sense stress and how this signal leads to activation. Expected outcomes include the generation of fundamental knowledge in immunology and structural biology. This proposal uses high-ski ....In depth characterisation of the gamma delta T cell immune synapse. This project aims to comprehensively characterise the activation principles of gamma delta T cells. These cells have an understudied but central role in vertebrate immunity and development. A missing piece of the puzzle is how gamma delta T cells sense stress and how this signal leads to activation. Expected outcomes include the generation of fundamental knowledge in immunology and structural biology. This proposal uses high-skilled techniques, including cryo-electron microscopy and single-molecule imaging and holds ancillary benefits to postgraduate students. Anticipated outcomes include influential publications, building a critical mass of expertise in Australia and fostering international collaborations with Australia at the epicentre.Read moreRead less
Characterising The Beta-catenin Nuclear Targeting Pathway In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$485,081.00
Summary
Bowel cancer is caused by inherited gene mutations that cause build-up of beta-catenin protein in the cell nucleus. Bowel cancer is the second largest cause of cancer deaths in Australia. We aim to study the mechanisms controlling beta-catenin accumulation in the nucleus. We will characterise new signalling pathways that control movement and activity of beta-catenin in the nucleus. This will yield insights into the role of beta-catenin in cancer and possible targets for therapy.