Enhancing The Cardioprotective Effect Of Diadenosine Tetraphosphate: Designing Inhibitors Against Ap4A Hydrolase
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitocho ....Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitochondrial ATP-dependent potassium channel may be in common with most pathways. Pretreatment with the compound diadenosine tetraphosphate (Ap4A) mimics ischemic preconditioning with noticeable reductions in tissue necrosis (cell death). This treatment has been shown in experimental work to protect the heart during periods of stress such as in heart surgery or recovery from an ischemic event. The biological site of action by Ap4A may be the mitochondria ATP-dependent potassium channel or an associated protein. Ap4A can be degraded by enzymes located inside and on the outside of heart cells, notably by two forms of Ap4A hydrolase. We will use antibody assays to understand the specific localization and amount of Ap4A hydrolase before and after ischemia and after ischemic preconditioning in human heart muscle and blood vessels. We propose to determine the structure of the enzyme and use novel computer methods to screen databases for potential inhibitors. These inhibitors of Ap4A hydrolase activity could aid the design of a potent inhibitor that would prevent Ap4A hydrolase from degrading Ap4A and therefore enhance the cardioprotective properties of Ap4A as well as minimizing side effects from the break down of Ap4A. We will also use these inhibitors and other known non-degradable Ap4A analogues in bioassays to test the relative significance of Ap4A hydrolase present in different cellular locations.Read moreRead less
Towards A New Class Of Reverse Transcriptase Inhibitor For HIV Prevention
Funder
National Health and Medical Research Council
Funding Amount
$688,833.00
Summary
There remains an urgent need for new HIV prevention strategies. New HIV drugs that block the virus by distinct ways are needed to prevent transmission of drug resistant HIV. This study seeks to identify very small molecules called “fragments” that bind to previously undiscovered pockets on the HIV reverse transcriptase to stop its function, and that can be used as building blocks to design more potent HIV drugs to be used solely for HIV prevention.
Function And Inhibition Of Plasmepsin V In Targeting Malaria Virulence Proteins Into Human Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$407,845.00
Summary
Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cel ....Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cell.Read moreRead less
Mechanisms Underlying APOBEC3G Restriction Of HIV-1
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
In the fight against worldwide HIV-AIDS, understanding natural cell defenses to the HIV virus may identify new virus targets and strategies to block HIV in humans. Here, we will use state-of-the-art, high resolution, fluorescent microscopy to understand how the recently identified cell protein, APOBEC3G, blocks the HIV life cycle in human cells. We anticipate that APOBEC3G will stop HIV from invading the nucleus of human cells to defend against HIV, a strategy we can apply to new therapies.
Characterisation Of Eurl, A Novel Gene Implicated In The Etiology Of Abnormal Brain Development And Intellectual Disability
Funder
National Health and Medical Research Council
Funding Amount
$597,541.00
Summary
Intellectual disability affects around one per cent of Australians, and can arise from genetic abnormalities during fetal life, such as through abnormal regulation of gene expression. We have identified a novel gene, known as eurl, which controls brain assembly as well as the ability of neurons to form functional connections within the brain. We will investigate how this novel gene controls brain development, and characterise eurl as a potential therapeutic target for learning and memory.
Defining The Role Of The Ubiquitin Protein Ligase Nedd4 In Vascular Development.
Funder
National Health and Medical Research Council
Funding Amount
$702,166.00
Summary
Blood and lymphatic vessels are vital components of the cardiovascular system. Abnormalities in the growth and development of these vessels are associated with human disorders including cancer and cardiovascular disease. The focus of this application is to characterise the role of the ubiquitin protein ligase Nedd4 in vascular development, with the aim of identifying targets to which novel therapeutics for the treatment of blood and lymphatic vascular diseases could be generated.
Learning for Teaching in Disadvantaged Schools. This project focuses on what and how primary school teachers learn about improving classroom practices from co-inquiry interventions. The effective diagnosis of student learning difficulties and the design of educational interventions based on such diagnosis is a core component of quality teaching. Yet many teachers have not acquired the knowledge and skills to undertake such learning diagnostic and design work. The project plans to engage practiti ....Learning for Teaching in Disadvantaged Schools. This project focuses on what and how primary school teachers learn about improving classroom practices from co-inquiry interventions. The effective diagnosis of student learning difficulties and the design of educational interventions based on such diagnosis is a core component of quality teaching. Yet many teachers have not acquired the knowledge and skills to undertake such learning diagnostic and design work. The project plans to engage practitioners in co-inquiry through collaborative analysis of professional learning conversations and classroom practices across disadvantaged public schools in urban and regional locations across Queensland. It aims to examine the sustainability of co-inquiry models to improve student learning.Read moreRead less
What is safe about “safe migration”? Migration management in the Mekong. The project seeks to examine the claims that new policy models make about assuring the safety of labour migrants. What is safe about safe migration? Regulation of labour migrants is a central policy concern in Asia, Australia and elsewhere. In an attempt to address anti-trafficking, several donors, United Nations agencies, nongovernment organisations and Governments have launched ‘safe migration’ programs which, rather than ....What is safe about “safe migration”? Migration management in the Mekong. The project seeks to examine the claims that new policy models make about assuring the safety of labour migrants. What is safe about safe migration? Regulation of labour migrants is a central policy concern in Asia, Australia and elsewhere. In an attempt to address anti-trafficking, several donors, United Nations agencies, nongovernment organisations and Governments have launched ‘safe migration’ programs which, rather than focusing solely on the legal status of migrants, seek to develop mechanisms (eg hotline numbers) to assure their safety. This research examines the claims of safety that this shift from anti-trafficking to safe migration has engendered, and whether and in what terms labour migrants might be consequently safer’. Project results may inform aid programs and government policies.Read moreRead less
Hedgehog Signalling In Limb And Craniofacial Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$494,544.00
Summary
Anomalies of the face and limbs are amongst the most common features of human birth defects, and their frequent association suggests that the same genes are involved in governing the development of the limbs and face during embryogenesis. We have used a genomics-based approach to identify genes involved in limb development based on their alteration in a mouse model which develops extra fingers and toes. Defects in this mouse result from changes in Gli3, a gene which is known to be important in b ....Anomalies of the face and limbs are amongst the most common features of human birth defects, and their frequent association suggests that the same genes are involved in governing the development of the limbs and face during embryogenesis. We have used a genomics-based approach to identify genes involved in limb development based on their alteration in a mouse model which develops extra fingers and toes. Defects in this mouse result from changes in Gli3, a gene which is known to be important in both limb and face development. Based on the organs in which our genes of interest are active, we believe that they will also play key roles in embryonic development of the limbs, face and other organs. We now plan to investigate the regulation of a subset of these genes based on analysis in mouse models of limb and face development. In addition, we have chosen to further analyse the function of a completely novel gene we have identified which our preliminary studies suggest may play a role in the normal development of the lip and palate. These studies have the potential to shed light on the processes governing how organs develop, as well as on the molecular basis of common birth defects such as polydactyly (extra fingers and toes) and cleft palate.Read moreRead less
Investigating A Theoretical Model Of Cognitive Control In Children With Attention Deficit Hyperactivity Disorder (ADHD): Informing Our Approach To Cognitive Training.
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
ADHD is the most common childhood developmental disorder, characterised by inattentive and/or hyperactive behaviours. Cognitive control has been highlighted as a potential mediator of ADHD symptoms. This program will i) delineate the relationship between cognitive control and ADHD symptoms, ii) develop a cognitive training intervention to target the underlying mechanisms identified as mediators of ADHD symptoms and iii) evaluate the program in a gold-standard clinical trial.