Perturbation of the extracellular architecture to promote the absorption and lymphatic transport of biological macromolecules. Macromolecules therapeutics such as proteins, antibodies or polymer conjugates pose a number of pharmaceutical challenges. Where the dose is high, drainage of that dose from a subcutaneous injection site into the circulation, poses a particular problem. Here the project aims to explore how recombinant hyaluronidase, an enzyme that breaks down a structural component (hya ....Perturbation of the extracellular architecture to promote the absorption and lymphatic transport of biological macromolecules. Macromolecules therapeutics such as proteins, antibodies or polymer conjugates pose a number of pharmaceutical challenges. Where the dose is high, drainage of that dose from a subcutaneous injection site into the circulation, poses a particular problem. Here the project aims to explore how recombinant hyaluronidase, an enzyme that breaks down a structural component (hyaluronan) of the interstitum, can be used promote absorption into the draining blood and lymph capillaries. The project aims to also explore the downstream effects of hyaluronidase on lymph nodes and evaluate whether the enzyme is able to temporarily disrupt the lymph node structure and promote drug penetration into the lymph node mass. This has significant potential for improved drug targeting.Read moreRead less
The Pharmacokinetic, Pharmacodynamic And Pharmacogenomic Outcomes Of Reduced Dosage Of Efavirenz: The Encore1 Study
Funder
National Health and Medical Research Council
Funding Amount
$1,234,943.00
Summary
Our primary aim is to assess blood concentrations of a drug called efavirenz, an important drug used in the treatment of HIV infection and associate these with variability of genes that control metabolism of the drug. A better understanding of gene variability and how it relates to safety and efficacy outcomes at a reduced, compared to a standard dose of efavirenz could support improved treatment of HIV disease.
Understanding the Cellular Pathways of Nuclear Receptor Activation. The success of drug treatment depends critically on specificity, i.e., stimulation of a therapeutic response at a target site, and avoidance of activity at other (potentially toxic) locations. This project aims to explore how drug interactions with binding proteins in the cytosol can induce nuclear transport and tissue specific activation of nuclear receptors - a major drug target. The project intends to employ molecular, struct ....Understanding the Cellular Pathways of Nuclear Receptor Activation. The success of drug treatment depends critically on specificity, i.e., stimulation of a therapeutic response at a target site, and avoidance of activity at other (potentially toxic) locations. This project aims to explore how drug interactions with binding proteins in the cytosol can induce nuclear transport and tissue specific activation of nuclear receptors - a major drug target. The project intends to employ molecular, structural and cell biology approaches to map drug-binding protein-receptor interactions and to determine how the structure of these complexes dictates receptor activation. The data could provide a roadmap to design drugs that interact with the right protein in the right tissue and in doing so dramatically enhance drug specificity.Read moreRead less
Controlling the spatial distribution of targeting ligands on dendrimer surfaces as a means of dictating cellular recognition and fate. This project seeks to develop next generation targeted drug delivery systems that 'home' to specific target cells, including cancers. Targeted delivery systems have the potential to revolutionise therapy by providing bespoke drug distribution patterns that are tailored to specific diseases and result in enhanced activity and reduced toxicity.
Molecular Pathogenesis Of Amino Acid Neurotransmission In Human Chronic Alcoholism
Funder
National Health and Medical Research Council
Funding Amount
$378,750.00
Summary
Brain damage resulting from long-term alcohol abuse is localized to discrete regions of the brain, and may selectively affect certain specific functions of nerve cells. It appears that alcoholism affects processes which control the excitability in discrete regions of the brain, and hence can cause them to be over-stimulated. It is known that if brain cells are excessively stimulated for long periods, they are in danger of being killed. This study will determine how the tissue s capacity to proce ....Brain damage resulting from long-term alcohol abuse is localized to discrete regions of the brain, and may selectively affect certain specific functions of nerve cells. It appears that alcoholism affects processes which control the excitability in discrete regions of the brain, and hence can cause them to be over-stimulated. It is known that if brain cells are excessively stimulated for long periods, they are in danger of being killed. This study will determine how the tissue s capacity to process glutamate, the brain s major natural excitant, is altered in the regions which are selectively damaged in alcoholics. How these processes are affected by heredity, and by diseases commonly associated with alcoholism such as cirrhosis of the liver, will also be explored. An understanding of how selective brain damage occurs in alcoholics will help us to devise new drug therapies to combat and prevent it. As well, selective brain damage is found in a great many neurological diseases, so this study will provide a model which may help to dene general processes which give rise to localised neurological damageRead moreRead less
Computational And Structural Studies Of Protein-GPCR Interactions Underlying HIV Infection
Funder
National Health and Medical Research Council
Funding Amount
$408,768.00
Summary
While it is known that HIV entry and disease progression relies upon the interaction of a number of distinct proteins, the precise nature of these interactions remains unclear. The purpose of this fellowship is apply computational and experimental techniques to stabilise members of the protein complex so that we can understand their structure.
Discovery Early Career Researcher Award - Grant ID: DE120103084
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Targeting bacterial superbugs: novel approaches for optimisation of antibiotic combinations and resistance prevention. This project will elucidate the mechanistic basis to optimally combine available beta-lactam antibiotics to prevent resistance of gram-negative 'superbugs'. The interdisciplinary project will substantially contribute to solving the global crisis due to multidrug-resistant bacteria and inform the design of effective new antibiotics.
Targeting an impending global disaster: the mismatch between increasingly drug-resistant superbugs and development of new antibiotics. This project will develop much-needed novel antibiotics for treating infections caused by bacteria that are resistant to all current antibiotics. It will make a significant contribution to the global medical challenge of a shortage of new antibiotics.
The role of hyaluronan in antigen and immune cell trafficking. This project aims to examine how hyaluronidase, an enzyme that breaks down hyaluronan (a structural component of the skin), affects antigen and cell trafficking to lymph nodes. The project expects to generate new knowledge on the role of hyaluronan in antigen presentation and immunity and to build an interdisciplinary collaboration across immunology, lymphatic transport and material science. The expected outcomes of the project are t ....The role of hyaluronan in antigen and immune cell trafficking. This project aims to examine how hyaluronidase, an enzyme that breaks down hyaluronan (a structural component of the skin), affects antigen and cell trafficking to lymph nodes. The project expects to generate new knowledge on the role of hyaluronan in antigen presentation and immunity and to build an interdisciplinary collaboration across immunology, lymphatic transport and material science. The expected outcomes of the project are the development of new knowledge and new models to explore immunity, interdisciplinary training for researchers and post graduate students and a roadmap of the importance of hyaluronan in antigen trafficking. Read moreRead less
Cytochrome P450 CYP3A Regulation In Humanized Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$376,980.00
Summary
The study of the regulation of human genes is inherently difficult. It is difficult or impossible to gain access to many body tissues in either healthy or sick individuals to examine coordinated gene function (or dysfunction). For this reason, it is often the case that we have a much better understanding of gene function in species such as rats and mice, the most common animal environments for biomedical research. However, findings in animals often fail to meaningfully mirror what occurs in man. ....The study of the regulation of human genes is inherently difficult. It is difficult or impossible to gain access to many body tissues in either healthy or sick individuals to examine coordinated gene function (or dysfunction). For this reason, it is often the case that we have a much better understanding of gene function in species such as rats and mice, the most common animal environments for biomedical research. However, findings in animals often fail to meaningfully mirror what occurs in man. To progress our understanding of human genes we need to develop models that more faithfully reproduce the human situation in an environment that is amenable to both manipulation and close examination, such as the novel 'humanised' mouse models described in this application. This application deals with the regulation genes that control liver enzymes belonging to the human cytochrome P450 3A (CYP3A) subfamily. These enzymes are present in several tissues including liver, gut, lung and breast. They form the main disposal pathway for foreign chemicals such as drugs, environmental pollutants and some cancer causing chemicals. In addition they are involved in the breakdown of several important internally produced substances, such as steroid hormones. Altered formation of CYP3A enzymes can have a dramatic impact on the action of many important drugs and may predispose to some forms of cancer. In this project, we will insert the genes for all four human CYP3A enzymes into mice. We expect that these 'humanised' mouse models will effectively enable the human situation to be studied in a convenient animal model and allow detailed studies to be performed. A knowledge of the mechanisms involved in CYP3A enzyme formation is of particular importance to the fields of drug and steroid metabolism (both in health and in disease states), liver diseases and foetal pharmacology. In addition, these models will provide a new and useful tool for drug development.Read moreRead less