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    Targeting The AGE-RAGE Axis In Diabetes Associated Atherosclerosis

    Funder
    National Health and Medical Research Council
    Funding Amount
    $542,859.00
    Summary
    Based on extensive preliminary data we porpose that the AGE intercation with RAGE plays an important role in diabetes associated atherosclerosis. We will perform studies using a soluble form of the receptor RAGE which will trap AGEs in the blood and tissues and thus prevent diabetes related blood vessel damage. Furthermore, we will investigate if RAGE receptor on inflammatory cells such as macrophages plays a pivotal role in blood vessel injury in diabetes.
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    Molecular Investigations Of The Neuroprotective Activity Of Estrogen, Phytoestrogens, And Phytosterols

    Funder
    National Health and Medical Research Council
    Funding Amount
    $270,872.00
    Summary
    Estrogen protects women from heart and brain disease but more women will spend over a third of their lives in the postmenopausal state, which is characterized by reduced estrogen levels. Many studies suggest that estrogen-like compounds produced by plants may provide health benefits and alleviate the symptoms of menopause. We investigate the protective effects of such compounds in nerve cells, to address the unmet need for safe and effective prevention and treatment of neurological diseases.
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    Funded Activity

    Role Of Circulating Advanced Glycation End Products (AGEs) In Diabetic Nephropathy: Effect Of Benfotiamine Intervention

    Funder
    National Health and Medical Research Council
    Funding Amount
    $465,000.00
    Summary
    Advanced glycation products (AGEs) are compounds formed by the addition of sugars to amino acids (the building blocks of proteins). The addition of sugars to proteins induces biological changes that have been implicated in the development of diabetic complications, especially diabetic kidney disease. AGEs are a diverse group of compounds and to date the exact role that specific AGEs play in the causation of diabetic kidney disease is still unclear. However, new methods are now available that all .... Advanced glycation products (AGEs) are compounds formed by the addition of sugars to amino acids (the building blocks of proteins). The addition of sugars to proteins induces biological changes that have been implicated in the development of diabetic complications, especially diabetic kidney disease. AGEs are a diverse group of compounds and to date the exact role that specific AGEs play in the causation of diabetic kidney disease is still unclear. However, new methods are now available that allow the comprehensive quantification of individual AGE levels in blood. Our study involves the comparison of AGE blood levels, as a group or as specific AGEs with markers of diabetic kidney disease such as albumin (protein) excretion in the urine and the rate that the kidney filters the blood to form urine (glomerular filtration rate). Benfotiamine is a thiamine (vitamin B1) derivative that has been shown to decrease the formation of AGEs and to prevent kidney disease in diabetic animals. The present clinical study will assess whether benfotiamine has similar effects on AGEs and kidney disease in patients with type 2 diabetes. If successful, this study has the potential to provide a new treatment strategy for diabetic kidney disease in humans.
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    Funded Activity

    Restricting Dietary Advanced Glycation End Product Intake As A Potential Therapeutic Tool In Diabetic Nephropathy.

    Funder
    National Health and Medical Research Council
    Funding Amount
    $483,351.00
    Summary
    Kidney disease is a serious complication of diabetes and may occur as a result of a biochemical process known as advanced glycation. These advanced glycation end products (AGEs) accumulate in the kidney causing disruption of function. Due to modern food processing techniques, the Australian diet has a high AGE content. Over-eating foods which are high in AGEs may worsen diabetic kidney disease. This proposal will test the effects of dietary AGE restriction and overfeeding on kidney function.
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    Funded Activity

    Mast Cells - Bystanders Or Instigators Of Airway Remodelling In Asthma?

    Funder
    National Health and Medical Research Council
    Funding Amount
    $623,764.00
    Summary
    Current asthma treatments have little effect on changes to the breathing tubes in our lungs. The tubes are thickened and stiffer, with more muscle, blood vessels, matrix and mucus. We propose that a particular inflammatory cell, called a mast cell, causes these changes to the breathing tubes and we will find out how it does that. Thus this project will establish why and how the changes to the breathing tubes happen in asthma and reveal how best to target and reverse-prevent them in the future.
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    Circulating Low -molecular Weight AGEs In The Development And Progression Of Diabetic Complications

    Funder
    National Health and Medical Research Council
    Funding Amount
    $297,523.00
    Summary
    High levels of sugars seen in patients with diabetes leads to damage of many organs including the heart, the eyes and the kidneys. These high sugars cause damage through a number of mechanisms, one being the formation of advanced glycation end products or AGEs, formed by the irreversible reaction between proteins and glucose. This reaction leads to a change in the shape and function of AGE-modified molecules that progressively contributes to organ damage. AGEs also bind and activate specific rec .... High levels of sugars seen in patients with diabetes leads to damage of many organs including the heart, the eyes and the kidneys. These high sugars cause damage through a number of mechanisms, one being the formation of advanced glycation end products or AGEs, formed by the irreversible reaction between proteins and glucose. This reaction leads to a change in the shape and function of AGE-modified molecules that progressively contributes to organ damage. AGEs also bind and activate specific receptors that promote the damage and scarring of tissue. Where the glucose concentration is high, AGEs accumulate much more quickly. This is one reason why patients with good sugar control do better than those who are unable to control their blood sugars. The importance of this AGE pathway is illustrated by the fact that blocking the formation of AGEs is able to prevent kidney damage in animals with diabetes. In addition, exposure to AGEs can cause diabetes-like changes in the absence of high sugars. Our laboratory is a world leader in the study of the advanced glycation and methods blocking this process. The research proposed will investigate circulating levels of AGEs in experimental animals and patients with diabetes, and correlate them with the development and progression of complications of diabetes
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    Funded Activity

    Mechanisms Of Immune Complex-mediated Inflammation In The Cerebral Microvasculature

    Funder
    National Health and Medical Research Council
    Funding Amount
    $146,500.00
    Summary
    Immune complexes are formed when an antibody binds to the molecules it is directed against. Normally, this is important for fighting infection. However in some autoimmune diseases, inappropriate formation of immune complexes can be damaging to our own tissues. This damage occurs because immune complexes attract white blood cells to the areas where they form. Many tissues can be affected by this process. However, we know very little about the effects of immune complexes specifically in the brain. .... Immune complexes are formed when an antibody binds to the molecules it is directed against. Normally, this is important for fighting infection. However in some autoimmune diseases, inappropriate formation of immune complexes can be damaging to our own tissues. This damage occurs because immune complexes attract white blood cells to the areas where they form. Many tissues can be affected by this process. However, we know very little about the effects of immune complexes specifically in the brain. This is important because immune complexes are found in the brain in diseases such as lupus. Therefore the aim of this proposal is to determine how immune complexes induce damaging inflammation in the brain.
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    Funded Activity

    Regulation Of Nuclear Import Of Viral Oncoproteins And Transcription Factors By Protein-protein Interactions

    Funder
    National Health and Medical Research Council
    Funding Amount
    $650,383.00
    Summary
    The present application examines the controls that exerted over proteins that localize in the nucleus of eukaryotic cells. This relates relates integrally to cellular processes such as growth, development and oncogenesis. This research area is not represented elsewhere in Australia, and the particular experimental strategies to approach the problem, revolving around the use of special quantitative microscopic techniques are novel internationally. One part of the application seeks to examine tran .... The present application examines the controls that exerted over proteins that localize in the nucleus of eukaryotic cells. This relates relates integrally to cellular processes such as growth, development and oncogenesis. This research area is not represented elsewhere in Australia, and the particular experimental strategies to approach the problem, revolving around the use of special quantitative microscopic techniques are novel internationally. One part of the application seeks to examine transport within the cell of complexes of interacting proteins, rather than single proteins, under as close as possible to physiologically relevant conditions. This will be truly unique, and of great importance to our comprehension of eukaryotic cell function. This application examines particular types of negative control over protein nuclear localization. Since many proteins show such regulation, and in particular important proteins controlling cell growth and division, the results are fundamentally important to our understanding of how cells function in general. Further, this understanding may be applied in disease situations, such as viral-mediated oncogenesis. In the work we propose to do, viral proteins with functions relating to cancer will be examined in detail, as well as a cellular protein which is recognised by them - the tumor suppressor Rb. We intend to examine several viral oncoproteins which target Rb; one is a protein (E7) from the Human Papilloma Virus which has been frequently associated with cervical carcinomas and other cancers. Accordingly, the results may have direct application to viral-induced cancer, and our work may lead to understanding of the regulation of protein transport to the nucleus. This may thus afford a new approach at the pharmacological level to combat transformation.
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