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KYNURENINE PATHWAY METABOLOMIC PROFILING IN THE PROGRESSION OF MULTIPLE SCLEROSIS: DEVELOPMENT OF NOVEL BIOMARKER TO ASSESS DISEASE SEVERITY AND THERAPEUTIC REGIMEN
Funder
National Health and Medical Research Council
Funding Amount
$450,750.00
Summary
A metabolic process known as the kynurenine pathway (KP) has been found to be dysregulated in multiple sclerosis (MS) patients. We are currently investigating which components of the KP is impaired that put MS patients in jeopardy. Next, we aim to use specific drugs known to manipulate the KP in order to rectify the impairment and stop MS. Outcome of this study may potentially lead to discovery of new biomarkers to assess severity of MS progression and also novel therapeutic regimen.
The Involvement Of The Kynurenine Pathway In Blood Brain Barrier Disruption And Its Relevance For Neuroinflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$597,797.00
Summary
We aim to study the involvement of molecules deriving from the degradation of the essential amino acid tryptophan on the breakdown of the ñblood-brain barrierî (the cellular wall separating blood and brain) that is observed in several major brain diseases. Using specific drugs blocking the production or the effects of these toxic compounds we expect to be able to preserve the integrity of the blood brain barrier and so to limit brain inflammation and neuronal loss.
Role Of Kynurenine Metabolites In Causing And Preventing Excitotoxic Brain Damage In The Fetus.
Funder
National Health and Medical Research Council
Funding Amount
$92,815.00
Summary
Brain damage is present in some babies at birth, and recent epidemiological and clinical studies strongly suggest that this either occurs some time during the pregnancy, or the conditions are such that the fetal brain is particularly vulnerable to the stresses that are present during labor and birth. In this project we propose that hypoxic (low oxygen) conditions in the womb, either alone or in combination with substances released because of maternal infection, cause accumulation of a neurotoxic ....Brain damage is present in some babies at birth, and recent epidemiological and clinical studies strongly suggest that this either occurs some time during the pregnancy, or the conditions are such that the fetal brain is particularly vulnerable to the stresses that are present during labor and birth. In this project we propose that hypoxic (low oxygen) conditions in the womb, either alone or in combination with substances released because of maternal infection, cause accumulation of a neurotoxic substance - QUINOLINIC ACID - in the fetal brain and circulation. The increased production of QUINOLINIC ACID occurs because certain cells react to the low oxygen and infectious conditions - these cells include MICROGLIA, a cell type in the brain. Little is currently known about MICROGLIA in the developing brain. We will therefore study the effects of hypoxia and infection in fetal sheep, and we will determine how these conditions affect MICROGLIA and the synthesis of QUINOLINIC ACID in the fetal brain. The capacity of the brain to produce QUINOLINIC ACID is closely related to the dietary intake of the essential amino acid TRYPTOPHAN, and it is decreased when synthetic analogues of tryptophan are infused. Therefore, we have devised a treatment regime using these tryptophan analogues to prevent increases of QUINOLINIC ACID concnetrations in the fetal brain, and we propose that a simple treament is at hand to reduce the incidence of perinatal brain damage in human pregnancies.Read moreRead less
Regulation And Activity Of Fatty Acid Delta-6 Desaturase (D6D)
Funder
National Health and Medical Research Council
Funding Amount
$527,683.00
Summary
Fish and fish oils contain fats known as omega-3 fats. These have health benefits in adult conditions such as rheumatoid arthritis and heart disease, and they are necessary for proper brain and eye development in infants. However, much of the population does not like to eat fish and also, world fish stocks are under stress. Thus, a sustainable alternative source of omega-3 fats needs to be explored. Some vegetable oils such as canola, echium, and flaxseed oils have omega-3 fats. However, these a ....Fish and fish oils contain fats known as omega-3 fats. These have health benefits in adult conditions such as rheumatoid arthritis and heart disease, and they are necessary for proper brain and eye development in infants. However, much of the population does not like to eat fish and also, world fish stocks are under stress. Thus, a sustainable alternative source of omega-3 fats needs to be explored. Some vegetable oils such as canola, echium, and flaxseed oils have omega-3 fats. However, these are not the same as the omega-3s in fish oil. In general, vegetable omega-3s are known as short-chain omega-3s whereas those in fish are long-chain. When the vegetable oil omega-3s are consumed in the diet, the body must convert them to the fish-type, or long-chain, omega-3s in order to gain the health benefits. Currently, human metabolism is poor at doing this conversion. Our studies suggest that the amounts and blends of fats in most diets are well below optimal for conversion to long-chain omega-3s in the body. In particular, our studies show that there may be no point in simply adding more vegetable omega-3 fats to the diet. This project will examine the enzymes that convert the short-chain to the long-chain omega-3 fats. In particular, it will examine how the dietary fats interact with each other in detrimental ways to suppress activity of the conversion enzymes necessary for long-chain omega-3 formation. Evidence for the health benefits of fish-based omega-3 fats is very strong and it is an approach to health that most people can undertake on their own. Our lack of knowledge of the best way to use plant-based omega-3 fats is a large impediment for a more sustainable and broader based use of omega-3 fats. The results from this study will begin to fill in this knowledge gap. The results will be useful across a range of activities that are determinants of the kinds of fat that we eat. These include oil seed breeding, food manufacture, and dietetics.Read moreRead less
Fatty Acid Biosynthesis In The Malaria Chloroplast As A Drug Target
Funder
National Health and Medical Research Council
Funding Amount
$131,035.00
Summary
Malarial parasites contain a chloroplast similar to that of plants. We recently found genetic evidence suggesting the malaria chloroplast makes fats in the same way as plant chloroplasts. Additionally, we have found that drugs and herbicides that block plant chloroplast fat production stop growth of malaria cultures. Parasitologists had assumed that malaria was unable to make fats and would scavenge them from its human host so we have probably discovered a new metabolic pathway in these parasite ....Malarial parasites contain a chloroplast similar to that of plants. We recently found genetic evidence suggesting the malaria chloroplast makes fats in the same way as plant chloroplasts. Additionally, we have found that drugs and herbicides that block plant chloroplast fat production stop growth of malaria cultures. Parasitologists had assumed that malaria was unable to make fats and would scavenge them from its human host so we have probably discovered a new metabolic pathway in these parasites. We now propose to prove that the drugs work by blocking essential, chloroplast-based fat production in parasites. This could lead to novel treatment of malaria and related parasites.Read moreRead less