Understanding The Role Of Human Lens UV Filters In Age-Related Cataract
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Cataract is the most common cause of blindness worldwide, The cause of cataract is currently unknown and the only treatment available at present is surgery. This represents a huge burden on the Health budgets of all developed nations, including Australia. It has been estimated that if a treatment could be developed that simply delayed the onset of cataract by 10 years, the need for surgery would be halved. The savings to the Health budget in the USA alone would be approximately $2 billion (US). ....Cataract is the most common cause of blindness worldwide, The cause of cataract is currently unknown and the only treatment available at present is surgery. This represents a huge burden on the Health budgets of all developed nations, including Australia. It has been estimated that if a treatment could be developed that simply delayed the onset of cataract by 10 years, the need for surgery would be halved. The savings to the Health budget in the USA alone would be approximately $2 billion (US). We believe, on the basis of our previous research, that human lens UV filter compounds play a major role in the protein modification that is the hallmark of age-related cataract and indeed may be the key factor in precipitating cataract. This proposal seeks to confirm this hypothesis. If this theory is confirmed, it opens the door to pharmacological intervention for cataract by, for example, treating patients (or possibly all people in middle age) with drugs that inhibit the synthesis of the UV filter compounds.Read moreRead less
Probing The Structure, Mechanism And Inhibition Of Indoleamine 2,3-Dioxygenase Using Structure- And Ligand-Based Studies
Funder
National Health and Medical Research Council
Funding Amount
$319,650.00
Summary
The human enzyme indoleamine 2,3-dioxygenase (IDO) is responsible for the initiation of a major enzymatic pathway, known as the kynurenine pathway. During certain immune and infectious diseases IDO becomes over-active and this leads to accumulation of neurotoxic kynurenine pathway compounds (metabolites). The elevated levels of these metabolites have been linked to severe mental deterioration associated with diseases such as AIDS (AIDS dementia complex), malaria and Alzheimer's disease. Several ....The human enzyme indoleamine 2,3-dioxygenase (IDO) is responsible for the initiation of a major enzymatic pathway, known as the kynurenine pathway. During certain immune and infectious diseases IDO becomes over-active and this leads to accumulation of neurotoxic kynurenine pathway compounds (metabolites). The elevated levels of these metabolites have been linked to severe mental deterioration associated with diseases such as AIDS (AIDS dementia complex), malaria and Alzheimer's disease. Several kynurenine pathway metabolites have also been linked to age-related nuclear cataract, which is the major cause of human blindness. This project employs a multidisciplinary approach that brings together a team of expert scientists from medicinal chemistry, protein crystallography, protein biochemistry and neurology. The overall aims of the project are to determine the structure of IDO using the recombinant human enzyme that we have cloned and expressed in an active form and to develop compounds that will regulate levels of the kynurenine pathway metabolites by selectively inhibiting the action of IDO. In addition, we will begin to assess the medicinal value of the best inhibitors. We have already synthesised several inhibitors of IDO, but wish to design more potent inhibitors. In order to do this, computer-aided molecular modelling and X-ray crystallography (which effectively provides a picture of the enzyme with the inhibitors attached) will be used to predict the best molecular features needed for inhibition. This will greatly aid the design of new inhibitor compounds, which will then be synthesised. The best inhibitors will also be examined to determine their general pharmacological value and specifically their ability to treat AIDS dementia complex and age-related nuclear cataract. These enzyme inhibitors also have the potential to treat other significant human diseases.Read moreRead less