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Field of Research : Pharmacology and Pharmaceutical Sciences
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    Expression And Regulation Of Human Genes Central To Drug Disposition In The Brain

    Funder
    National Health and Medical Research Council
    Funding Amount
    $339,375.00
    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). This is particularly true for the brain, where live human tissue is unavailable. 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. H .... 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). This is particularly true for the brain, where live human tissue is unavailable. 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 in brain 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 'humanized' mouse models described in this application. This application deals with the genes that control enzymes belonging to the human cytochrome P450 3A (CYP3A) subfamily and the drug transporter MDR1. These genes are present in several tissues including liver, gut, lung and brain. 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. We postulate that altered formation of CYP3A enzymes and MDR1 in brain can have a dramatic impact on the action of many important drugs and may affect the way the brain responds in a behavioral sense to hormones, such as sex steroids. In addition, this work will provide a new and useful information relevant to the design and development of the plethora of drugs that act on the central nervous system.
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    Funded Activity

    Novel Peptides For The Treatment Of Pain

    Funder
    National Health and Medical Research Council
    Funding Amount
    $303,828.00
    Summary
    Chronic pain affects 1 in 5 Australians and neuropathic pain is among the most severe forms of chronic pain. Several peptides derived from cone snail venoms have attracted recent attention as potential therapeutic agents for the treatment of neuropathic pain. One of these, conotoxin MVIIA, has recently been approved in the US and Europe and others, including CVID and ACVI, are in various stages of clinical investigation. These small disulfide rich peptides share the attractive features of peptid .... Chronic pain affects 1 in 5 Australians and neuropathic pain is among the most severe forms of chronic pain. Several peptides derived from cone snail venoms have attracted recent attention as potential therapeutic agents for the treatment of neuropathic pain. One of these, conotoxin MVIIA, has recently been approved in the US and Europe and others, including CVID and ACVI, are in various stages of clinical investigation. These small disulfide rich peptides share the attractive features of peptides in general of having exquisite selectivity for particular receptors, but also share the general disadvantages of peptides of short biological half-lives and poor bioavailablility. Stabilisation of these conotoxins has the potential to substantially increase their therapeutic potential. In preliminary studies we have shown that by introducing a circular petide backbone into a conotoxin using a linker sequence we can increase its stability and resistance to enzymatic degradation. We therefore propose that it will be possible to cyclise a wide range of conotoxin molecules and thereby improve their drug like properties. In this project we will use our cyclisation approach to develop new potential treatments for pain from two classes of conotoxins. One of the lead molecules shows oral bioavailability in an animal pain model and potentially represents a major breakthrough in the field of peptide drug delivery.
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    Funded Activity

    Linkage Projects - Grant ID: LP0669667

    Funder
    Australian Research Council
    Funding Amount
    $249,000.00
    Summary
    Topical peptide delivery for cosmetic and therapeutic benefits. Milk is a major Australian agricultural commodity and is now used in a number of topical products for the management of various skin conditions including chafing in babies, eczema and ageing skin. Hence, this work hopes to contribute to promoting and maintaining good health of Australians. In addition, there is considerable research being conducted on peptide development for a range of diseases and there may be a possibility of .... Topical peptide delivery for cosmetic and therapeutic benefits. Milk is a major Australian agricultural commodity and is now used in a number of topical products for the management of various skin conditions including chafing in babies, eczema and ageing skin. Hence, this work hopes to contribute to promoting and maintaining good health of Australians. In addition, there is considerable research being conducted on peptide development for a range of diseases and there may be a possibility of delivering these by the skin. This work, in seeking to understand some of the fundamental determinants governing how exogenously applied peptides distribute in the skin, is also contributing to the development of Australian pharmaceutical and cosmetic industries.
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    Funded Activity

    Pharmacogenetic Investigations Of Glutathione Transferases

    Funder
    National Health and Medical Research Council
    Funding Amount
    $471,000.00
    Summary
    Members of the family of enzymes known as glutathione transferases are known to be responsible for the metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response to drug treatment or their susceptibility to cancer. This study will investigate (1)the genetic mechanisms that alter the production of glutathione transferases, (2) the character .... Members of the family of enzymes known as glutathione transferases are known to be responsible for the metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response to drug treatment or their susceptibility to cancer. This study will investigate (1)the genetic mechanisms that alter the production of glutathione transferases, (2) the characteristics of a new class of glutathione transferases and (3) the role of glutathione transferase A4 in protecting against disorders such as atherosclerosis and Parkinson's disease.
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