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The Bcl-2 family of proteins is crucial for apoptosis (a form of programmed cell death) regulation. They target the mitochondrial outer membrane where they interact to determine cell fate. We will evaluate the membrane interactions of the Bcl-2 proteins in complementary biophysical and cellular experiments to redefine our understanding of the mechanism of apoptosis and provide new avenues for the development of compounds to selectively modulate diseases in which apoptosis is unregulated.
Mechanism Of Bacterial Resistance To Antimicrobial Peptides
Funder
National Health and Medical Research Council
Funding Amount
$675,585.00
Summary
Bacterial resistance to antibiotics continues to emerge and intensify. While antimicrobial peptides (AMPs) are a promising alternative to current antibiotics, bacteria have also evolved resistance mechanisms to them through changes in their cell membrane. This application will apply a range of analytical and biophysical tools to understand how bacteria change their cell walls in response to AMPs. The results will allow us to design new combination therapies to treat bacterial infections.
Amyloid Precursor Protein Signalosome: Directing Abeta Production In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$681,459.00
Summary
Alzheimer's disease is the most common form of dementia and is the fourth biggest killer in developed countries. Amyloid precursor protein plays a central role in the development of the disease, through the generation of a toxic peptide called Abeta. In this project we will decipher the fine molecular details of what the protein looks like and how various molecules known to bind to it affect Abeta production. This knowledge is expected to lead to novel therapies to treat the disease.
Integrative Systems Pharmacology, Neutron Reflectometry And Molecular Dynamics Approaches To Unravelling The Interactions Between Polymyxins And Bacterial Membranes
Funder
National Health and Medical Research Council
Funding Amount
$968,005.00
Summary
Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii are among the 6 top-priority dangerous ‘superbugs’ causing life-threatening infections worldwide. This study will employ a multi-disciplinary approach to decipher the complex interactions of polymyxins with the membranes of these three ‘superbugs’ and to discover novel antibiotics with superior efficacy. This innovative project targets the urgent unmet global medical crisis due to antibiotic resistance.
The hormone angiotensin II (AngII) contributes broadly to the cardiovascular, endocrine, neural and metabolic systems. It binds to the angiotensin II type 1 (AT1) receptor and inappropriate activity leads to hypertension. Using a range of molecular and biophysical approaches and the angiotensin receptor as a model GPCR, we will study the role of the cell membrane in AT1 activation which may lead to new approaches for drug design.
A New Class Of Anti-Malarial Agents Targetting Apical Membrane Antigen
Funder
National Health and Medical Research Council
Funding Amount
$597,598.00
Summary
Malaria is a major global health problem that imposes a substantial burden on the world’s most vulnerable societies. The invasion of host cells by malaria parasites represents an attractive target for therapeutic intervention, and Apical Membrane Antigen 1 (AMA1) plays an essential role in this process. Agents that bind to a key interaction site on AMA1 prevent host cell invasion and thus represent starting points for the development of a new class of anti-malarial drugs.
The brain exerts a restraining influence over the heartbeat via the vagus nerves. This is known as cardiac vagal ‘tone’. It is strong when we are healthy but weak when we are sick. It has a positive influence on the health of the heart and perhaps the body generally. Vagal tone comes from the brain but, despite over 150 years’ research, nobody knows exactly where. Using a novel technique, we can track down its origins. This important basic knowledge may lead to ways to improve health.
A New Animal Model Of The Prodrome In Schizophrenia. Enhanced Dopamine In Prodromal Schizophrenia (EDiPs)
Funder
National Health and Medical Research Council
Funding Amount
$571,990.00
Summary
Psychiatrists now recognize a pre-symptomatic stage is present in people at risk of developing schizophrenia. Using new brain imaging techniques we now know that some of these individuals have changes in a major neurotransmitter, dopamine, prior to being diagnosed. We have developed a new model in animals, which recreates these exact same changes at a comparable age. We want to now understand what are the broader effects in the brain and try and block these changes in dopamine with new drugs.
Mechanical Factors In Normal Human Colonic Motility
Funder
National Health and Medical Research Council
Funding Amount
$650,023.00
Summary
Abnormal human colonic contractions cause significant medical, societal and financial burdens. Diagnosis and treatment of motility disorders requires an understanding of normal colonic contractility against which to measure dysfunction. Through state-of-the-art recording and analytical techniques, developed by the applicants, this project will provide the first clear description of normal human colonic motor patterns and how they are generated.
Localised Airway Reactivity As A Determinant Of Asthma Control And AHR
Funder
National Health and Medical Research Council
Funding Amount
$306,562.00
Summary
Asthma morbidity and mortality remain high, with drug cost, days lost from school and work. This may be due to severe asthma in which control cannot be attained. This may be due to localised regions of lung that remain persistently responsive to inhaled irritants. We will examine the location and size of these regions using 3-dimensional ventilation scanning. The potential importance of our findings is in providing a basis for improving treatment in resistant, severe asthma.