Physiological Effects Of Manipulating AMPK Signalling Genes
Funder
National Health and Medical Research Council
Funding Amount
$377,250.00
Summary
The AMP activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and switches on metabolic processes to restore energy. This includes stimulating glucose uptake and burning fat. With training the AMP activated protein kinase also controls genes to adapt the body to future exercise. Reducing caloric intake activates the A ....The AMP activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and switches on metabolic processes to restore energy. This includes stimulating glucose uptake and burning fat. With training the AMP activated protein kinase also controls genes to adapt the body to future exercise. Reducing caloric intake activates the AMP activated protein kinase to suppress energy consuming activities and modify the expression of genes. This enzyme is a powerful regulator of lipid metabolism, inhibiting both cholesterol and triglyceride synthesis. Many conditions that activate the AMP activated protein kinase (exercise, reduced caloric intake) are associated with a healthy lifestyle, increased longevity and resistance to age onset diseases including cardiovascular disease (atherosclerosis, hypertension), obesity, neurodegeneration and diabetes. It has been found that metformin and rosiglitizone, major drugs used to treat people with type II diabetes activate the AMP activated protein kinase. By manipulating the genes for the AMP-activated protein kinase in mice we expect to gain new insights into the physiological roles of this enzyme and how it functions to protect the body from age onset diseases.Read moreRead less
Understanding The Role Of B Cells In Gastric Cancer For The Design Of New Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$696,383.00
Summary
Gastric cancer is the 2nd most common cause of cancer-related death worldwide. Our laboratory has previously established clinically relevant mouse model of gastric cancers, and our preliminary results indicate a strong link between B cell tumor infiltration and gastric cancer progression. In this project, we aim to elucidate the role of B cells in gastric cancer and determine whether B-cell targeted therapy alone or in combination with chemotherapy can be beneficial against this malignancy.
Novel Signalling Pathways Leading To The Activation Of Glomerular Parietal Epithelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$408,768.00
Summary
Chronic kidney disease (CKD) is a major health problem in Australia. CKD patients have very limited therapeutic options. The majority of diseases that lead to CKD are associated scarring of the renal filters. Parietal epithelial cells reside in these filters and play key roles in scarring development. However, the molecular mechanisms that lead to scarring in these renal filters remain unclear. This proposal aims to identify molecular pathways that may serve as future therapeutic targets.
Robotic Surgical System For Image Guided Non-invasive Focused Ultrasound Induced Ablation Of Liver Cancers
Funder
National Health and Medical Research Council
Funding Amount
$582,231.00
Summary
According to National Cancer Institute, liver and bile duct cancers are the fifth most common cancer in men and the seventh in women. Due to poor prognosis involving surgery, radiotherapy and chemotherapy, our aim is to develop a novel image-guided, radiation-free, non-invasive robotic HIFU system with means for compensation of organ movement during treatment. The objective is to produce damage to the target in a predictable and reproducible manner while sparing overlying surrounding tissues.
The Developmental Vitamin D Model (DVD) As An Animal Model For Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$258,075.00
Summary
Most Australians have the opportunity to enjoy the natural benefits of sunlight, however many Australians lack vitamin D. We have shown that even in Queensland, the so-called Sunshine State, vitamin D levels in the middle of winter are below World Health Organisation recommended levels. We are exploring low maternal vitamin D as a biological explanation for the universal phenomena worldwide of a 7-10% increase in the incidence of patients born with schizophrenia in the colder months of the year. ....Most Australians have the opportunity to enjoy the natural benefits of sunlight, however many Australians lack vitamin D. We have shown that even in Queensland, the so-called Sunshine State, vitamin D levels in the middle of winter are below World Health Organisation recommended levels. We are exploring low maternal vitamin D as a biological explanation for the universal phenomena worldwide of a 7-10% increase in the incidence of patients born with schizophrenia in the colder months of the year. Schizophrenia is a developmental disease that presents in adolescence and affects about 1% of the world's population. To date we have shown increased amounts of schizophrenia in offspring from mothers that had low blood vitamin D levels during pregnancy or who had inadequate vitamin D intake. Early signs therefore appear promising but obviously more research is required to confirm this idea. Our studies in animals have revealed that by restricting vitamin D intake in pregnant rats, newborns have brains that develop differently. Most notably lateral ventricle volume is increased, a key anatomical finding in patients with schizophrenia. When these animals become adults the increase in lateral ventricles persists. Also when we explore the behaviour of these animals we find a deficit in learning and memory similar to that seen in many schizophrenic patients. Furthermore when we expose these animals to agents that induce psychosis or agents that block psychosis in patients we see a heightened sensitivity in animals that were deprived of this vitamin in utero particularly in locomotion. These behavioural findings are consistent with the best animal models for schizophrenia. At a mechanistic level they indicate an abnormality in the two major neurotransmitters in the brain that have been consistently linked with this disease, dopamine and glutamate. The experiments outlined in this application will attempt to establish the neurochemical basis for these altered behaviours.Read moreRead less
Genetic Adaptations Of Mycobacterium Tuberculosis For Intracellular Survival
Funder
National Health and Medical Research Council
Funding Amount
$187,677.00
Summary
Tuberculosis (TB) remains a significant global public health problem and new approaches to its treatment and prevention are urgently needed. The disease is caused by infection with Mycobacterium tuberculosis, a slow growing organism that lives within cells. How it adapts to survive in this intracellular environment is unknown. Recently the complete genome of M. tuberculosis was sequenced and new techniques developed for manipulating its genes. We plan to use these techniques to identify genes th ....Tuberculosis (TB) remains a significant global public health problem and new approaches to its treatment and prevention are urgently needed. The disease is caused by infection with Mycobacterium tuberculosis, a slow growing organism that lives within cells. How it adapts to survive in this intracellular environment is unknown. Recently the complete genome of M. tuberculosis was sequenced and new techniques developed for manipulating its genes. We plan to use these techniques to identify genes that are more active within the cells. Genes are controlled by short sequences of preceding DNA called promoters. If these promoters are randomly placed in front of readily identifiable reporter genes and inserted into a suitable host strain, it is possible to select for those promoters expressed only inside cells and then identify the promoter and its gene by sequence analysis. We plan to use two types of reporter genes. First, we shall place the M. tuberculosis DNA containing promoters before the gene for a naturally fluorescent protein within the M. bovis BCG host strain and then infect macrophages. If the promoters are switched on inside the cell, the macrophages will become green and can be selected and the promoter identified. After several rounds of selection the promoter is isolated and identified. Second, we shall select the promoters by their ability to produce a protein that is on the surface of the bacterium. We will use these intracellular genes to make better vaccines against TB. Genes that enhance intracellular survival may contribute to the virulence of the TB organism. By removing these genes we can make an attenuated organism suitable as a vaccine. We will test for reduced virulence by growth inside cells in mice. We will also use the intracellular promoter to improve the current BCG vaccine. Proteins expressed inside the cell may also be targets for new TB drugs.Read moreRead less
Clinical And Microbiological Predictors Of Post-operative Crohn's Disease Recurrence
Funder
National Health and Medical Research Council
Funding Amount
$120,253.00
Summary
The multi-centre randomised controlled POCER (Post-Operative Crohn’s Disease Recurrence) trial has shown that following “curative” surgery, the anti-tumour necrosis factor drug adalimumab prevents recurrent disease in almost all patients. I will examine the multiple factors that contribute to disease recurrence including assessment of mucosal microbiota, faecal biomarkers and serological antibody markers in patients with Crohn's disease. Results will improve clinical outcomes and change internat ....The multi-centre randomised controlled POCER (Post-Operative Crohn’s Disease Recurrence) trial has shown that following “curative” surgery, the anti-tumour necrosis factor drug adalimumab prevents recurrent disease in almost all patients. I will examine the multiple factors that contribute to disease recurrence including assessment of mucosal microbiota, faecal biomarkers and serological antibody markers in patients with Crohn's disease. Results will improve clinical outcomes and change international practice.Read moreRead less