Mechanism Of Interaction Of VWC Domains And Consequence For Protein Function
Funder
National Health and Medical Research Council
Funding Amount
$516,803.00
Summary
More than 1000 proteins contain a type of module known as the VWC domain. These domains are discreet sections of the protein that are very important for how the protein works. Proteins containing this domain are involved in normal functioning of the human body and in diseases of the nervous system and blood, among others. The main function of the VWC domain is to link proteins together in complexes. How this is achieved is not known and is what we aim to discover.
Understanding Age-related Protein Aggregation. The Mechanism Of Cataract And Its Prevention
Funder
National Health and Medical Research Council
Funding Amount
$709,333.00
Summary
Cataract arises from clouding of the eye lens due to the aggregation of crystallin proteins whose high concentration and close packing facilitate lens transparency. This proposal will investigate crystallin structure and interactions to understand the reasons for cataract formation and its prevention via the design of aggregation inhibitors. The results will facilitate the development of drugs to prevent cataract and other related protein aggregation diseases, e.g. Alzheimer’s and Parkinson’s.
Improving Synthetic Methodology To Prepare Pre-clinical Analogues Of Human Insulin
Funder
National Health and Medical Research Council
Funding Amount
$457,708.00
Summary
The glucose regulatory hormone, insulin, remains the only treatment for type I diabetes and up to 30% of type II diabetes, both of which are among the world’s fastest growing chronic diseases today. Because insulin, if taken orally, would be broken down quickly, it has usually been given by injection. This project will develop novel chemical methods for the efficient preparation of novel insulin therapeutics with improved stability and oral bioavailability for prolonged treatment of patients.
Chemical Aided Phospoproteome Sequencing With Mass Spectrometry
Funder
National Health and Medical Research Council
Funding Amount
$141,000.00
Summary
Essentially all of the body's functions from muscle contraction, energy expenditure through to appetite are controlled by a complex molecular communications system. One of the key elements involves the modification of proteins to alter their properties by adding and removing phosphate. By analysing this process in response to diet and exercise we will obtain a greater understanding of their health benefits and understand how type 2 diabetes and obesity develop at the molecular level.
Further Development Of The Clinical Potential Of H2 Relaxin
Funder
National Health and Medical Research Council
Funding Amount
$651,768.00
Summary
The hormone relaxin mediates cardiovascular and kidney changes during pregnancy. These important functions have led to its current use in clinical trials for the treatment of acute heart failure, a condition affecting millions of patients worldwide. However, there is an urgent need for a longer lasting form of relaxin for prolonged treatment of patients. Our studies will focus on understanding the blood breakdown of the peptide to lead to the design of longer lasting relaxin analogues.
Redefining The Pro-thrombotic Mechanism Of Von Willebrand Factor
Funder
National Health and Medical Research Council
Funding Amount
$750,005.00
Summary
Blood clotting is the underlying cause of heart attacks and strokes. The blood protein, von Willebrand factor, is a critical player in blood clotting and impairment of its function is life threatening. We have discovered that there are three forms of VWF in human blood that have different functions in blood clotting. Characterisation of these different forms will likely lead to new blood clotting diagnostics and improved therapies.
Investigating The Iron Proteome In Alzheimer’s Disease
Funder
National Health and Medical Research Council
Funding Amount
$514,644.00
Summary
Iron is essential for brain function. When the delicate balance of metals in the brain is disturbed, neurodegenerative effects such as those seen in Alzheimer’s disease are observed. Although we know there is a link between iron and Alzheimer’s disease, we do not know which specific iron proteins are involved. This project will provide the first characterisation of different iron proteins in the brain to understand the mechanisms of disease and help in the search for new treatments.
Mechanism Of Action And Targeting Of RAGE In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$386,423.00
Summary
Humans have evolved defense and repair mechanisms to counteract threats such as tissue injury and infection. The immune system first must detect the potential life-threatening event and it does so by recognizing danger signals. RAGE is a key cell-surface receptor that recognises these danger signals. Despite its important role in health and disease our understanding of how RAGE works is very limited. We will discover how RAGE works and how to manipulate its function for new infection therapies.
We propose to study the poorly understood, disease-associated process of amyloid formation, using a sensitive and reproducible model developed in our laboratory. Amyloid deposits are a feature of several neurodegenerative and metabolic disorders such as Alzheimer's and Parkinson's disease and are also common in atherosclerotic plaque or atheroma. They are composed of tangled networks of fibrillar proteins together with several non-fibrillar proteins and proteoglycans. Atherosclerotic plaques typ ....We propose to study the poorly understood, disease-associated process of amyloid formation, using a sensitive and reproducible model developed in our laboratory. Amyloid deposits are a feature of several neurodegenerative and metabolic disorders such as Alzheimer's and Parkinson's disease and are also common in atherosclerotic plaque or atheroma. They are composed of tangled networks of fibrillar proteins together with several non-fibrillar proteins and proteoglycans. Atherosclerotic plaques typically consist of fibrous proteins, lipids and foam cells derived from macrophages via receptor-mediated uptake of oxidized low density lipoproteins. Our model system is based on the formation of amyloid fibrils from apolipoprotein (apo) C-II which accumulates in atherosclerotic plaques where it co-localizes with serum amyloid P component, a marker of amyloid fibrils. ApoC-II is a component of plasma lipoproteins and an important activator of the enzyme lipoprotein lipase, which functions in the transport and distribution of triacylglycerols to tissues. We have shown that apoC-II (79 amino acids) readily forms amyloid fibrils under lipid-free conditions, adopting a cross-beta sheet structure that reacts with the amyloid stains thioflavin T and Congo Red. The formation and properties of apoC-II amyloid fibrils and the amyloid-like properties of oxidized lipoproteins are the subject of the present proposal. We will characterize the effects of lipids and oxidation on the rate of formation and the properties of apoC-II amyloid fibrils. We will also study the effects of oxidation on the amyloid-like properties of lipoproteins and their interactions with serum amyloid P component and cell surface receptors.Read moreRead less