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.Read moreRead less
Understanding The Side Effects Of HAART In HIV Patients
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
Combination therapy has dramatically improved the life expectancy of people living with HIV. However, the long term side effects of these medications can be significant. Not everyone treated with the same drugs suffers similar side effects. This project seeks to unravel factors that lead a given individual to experience particular side effects. Understanding why medication side effects occur will be critical in finding safer ways to treat HIV.
An Oral Loading Test To Predict Susceptibility To Fluoropyrimidine Drug Toxicity
Funder
National Health and Medical Research Council
Funding Amount
$225,525.00
Summary
Side-effects from anticancer drugs can be unpleasant, but may be deadly if a patient's genes are wrong for the drugs. A common chemotherapy drug, fluorouracil, can be very dangerous, but there's no simple way to predict this. We developed a simple test in which a small amount of a natural chemical is swallowed before chemotherapy. The results should allow the doctor to predict if a patient will suffer serious side effects on fluorouracil, so the dose can be reduced, or another drug tried.
Understanding The Mechanisms Of Functionally Selective Antipsychotic Drugs: Implications For New Generation Antipsychotic Drugs
Funder
National Health and Medical Research Council
Funding Amount
$371,745.00
Summary
Schizophrenia is a chronic and devastating disease that ranks among the top 10 disabilities in developed countries. It places a significant burden on the Australian health system, costing about $1.5 billion each year. This project aims to reveal the mechanisms of new functionally selective antipsychotic drugs, which achieve an excellent therapeutic efficacy with low side-effects. Understanding these mechanisms will provide novel directions for the design of new generation antipsychotic drugs.
New Drugs To Counteract The Side Effects And Premature Ageing Caused By Chemotherapy
Funder
National Health and Medical Research Council
Funding Amount
$577,658.00
Summary
During cancer treatment, commonly used chemotherapy drugs cause profound side effects that include pain, nausea, heart problems, hair loss and can affect almost every system in the body. Even after chemotherapy treatment has stopped, cancer survivors face an increased risk of diseases which resemble the effects of old age. We are testing newly discovered anti-ageing molecules for their ability to reduce these side effects, and drastically improve the quality of life for cancer patients.
Cyclotherapy: A New Approach To Stop The Side Effects Of Chemotherapy
Funder
National Health and Medical Research Council
Funding Amount
$565,847.00
Summary
Cyto-toxic chemotherapy is a widely used treatment for cancer but is associated with significant side effects for the patient. These are due to the chemotherapy killing normal dividing cells in the gut, bone marrow and hair follicles. We will determine the potential of cyclotherapy in preventing these side effects. In cyclotherapy a pre-treatment temporarily stops normal cells from dividing and therefore protects them from the damage of subsequent chemotherapy.
Understanding The Mechanisms For Ameliorating/preventing Antipsychotic-induced Obesity In Early Life
Funder
National Health and Medical Research Council
Funding Amount
$576,496.00
Summary
There has been a sharp worldwide increase during the last decade in antipsychotic prescriptions (mostly “off-label”) to paediatric patients. One important issue is that antipsychotic drugs were developed for adult patients and normally have serious side-effects. This project will not only reveal the mechanisms of antipsychotic-induced obesity side-effects in youth, but will also explore intervention strategies for preventing antipsychotic-induced weight gain/obesity in paediatric patients.
Roles Of Muscarinic M3 Receptors In Antipsychotic-induced Metabolic Side-effects: Prevention And Treatment Of Antipsychotic-induced Insulin Dysregulation
Funder
National Health and Medical Research Council
Funding Amount
$603,825.00
Summary
Antipsychotic drugs are used to treat various mental disorders, such as schizophrenia, bipolar disorder, dementia and major depression. However, these drugs cause serious metabolic side-effects leading to premature death and huge costs to the Australian health care system. This project aims to reveal the role of muscarinic M3 receptors in antipsychotic-induced insulin dysregulation that precedes diabetes. Understanding these mechanisms will provide new strategies for the prevention and treatment ....Antipsychotic drugs are used to treat various mental disorders, such as schizophrenia, bipolar disorder, dementia and major depression. However, these drugs cause serious metabolic side-effects leading to premature death and huge costs to the Australian health care system. This project aims to reveal the role of muscarinic M3 receptors in antipsychotic-induced insulin dysregulation that precedes diabetes. Understanding these mechanisms will provide new strategies for the prevention and treatment of these critical adverse effects.Read moreRead less
TIR Signalling Pathway Pharmacogenomics And Opioid Response: Beyond The Mu Opioid Receptor
Funder
National Health and Medical Research Council
Funding Amount
$246,396.00
Summary
This project will identify why some people respond poorly and others have toxic side effects to the major group of pain relieving medications, the opioids. The basis will be the genetics of the immune system and both acute postoperative and chronic cancer pain patients will be studied in this international pharmacogenetics project.
Optimising Outcomes In Chronic Myeloid Leukaemia Through Rational Drug Selection Using Predictive Assay Results And Maximising Treatment Free Remissions
Funder
National Health and Medical Research Council
Funding Amount
$193,596.00
Summary
Although outcomes in chronic myeloid leukaemia are generally excellent, a number of important questions remain. In this grant, we propose to i) personalise the selection of frontline treatment for newly diagnosed patients, using biomarkers which can predict treatment response; ii) improve the probability of cure in patients aiming to stop their treatment, and iii) use ultra-sensitive molecular tests for disease detection to predict risk of disease relapse.