Modulating Interactions Between TNFalpha And IGF-1 Signaling Pathways To Reduce Necrosis Of Dystrophic Muscle
Funder
National Health and Medical Research Council
Funding Amount
$476,515.00
Summary
Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attracti ....Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attractive options for treatment of DMD patients due to their high specificity of action and relatively few side effects. We have shown that both of these drugs have a striking protective effect and reduce necrosis of dystrophic muscle in the mdx mouse. The benefits of these drugs (and the mouse equivalent cVIq) is due to blocking the action of the key pro-inflammatory cytokine Tumour Necrosis Factor-alpha (TNFa). However, the precise mechanism by which high levels of TNFa increase necrosis of dystrophic muscle is not clear. There are many possible pathways. Identifying which is the key pathway(s), is of central importance to design and target new drugs to treat such lethal muscle diseases. Such modulation of signalling is a major therapeutic goal. To determine which mechanism of TNFa action is responsible for muscle necrosis, experiments will investigate several signalling pathways using specific inhibitors: the drug Pifithrin to inhibit p53; soluble RAGE to block RAGE (Receptor for Advanced Glycation Endproducts); and specific inhibitory peptides to block JNK (c-Jun N-terminal kinase). The application of these inhibitors (drugs), in mice, as future therapies for muscle diseases is novel. These studies will provide much new information on TNFa related signalling that is highly relevant to the potential treatment of many diseases, including muscle wasting that is a major problem in the ageing population and in disuse atrophy and cachexia.Read moreRead less
From Lead Compounds To Potential Therapeutics: Drugs To Treat Clostridium Difficile Infections
Funder
National Health and Medical Research Council
Funding Amount
$523,460.00
Summary
Clostridium difficile infection (CDI) attacks the gut resulting in diarrhoea and inflammation of the colon. It is classified as the number one antibiotic-resistant bacterial threat in the USA where there are 500,000 cases of CDI and 30,000 deaths. CDI is an increasing problem for hospitalized patients in the US, the EU and Australia. Our recent NHMRC funded project established drug leads against CDI and we now require continued studies to develop our drug leads towards marketable therapeutics.
I am an infectious diseases physician and basic scientist interested in the immunopathogenesis of HIV and hepatitis B virus. My work focuses on HIV viral reservoirs and immune reconstitution and the adaptive immune response to hepatitis B virus.
A Transgenic Approach To Rationale Drug Design In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
Malaria is a disease caused by parasites of the genus Plasmodium. It is responsible for more than 2 million deaths per year predominately in Sub-Saharan Africa. Many of the currently used drugs to combat this disease are failing through drug resistance in the parasite population. New and novel drugs are urgently required. This project uses state of the art techniques to identify and validate new and novel targets within the parasite that can be used for rational drug design
Can Esomeprazole Improve Outcomes In Women At High Risk Of Pre-eclampsia? A Phase II Placebo-controlled Randomised, Multi-centre Clinical Trial.
Funder
National Health and Medical Research Council
Funding Amount
$1,597,125.00
Summary
Pre-eclampsia, recognised through the development of high blood pressure in pregnancy, causes death and/or injury to mothers and babies. An improved understanding of the development of pre-eclampsia has provided opportunities for early prediction and prevention of disease. We will use a powerful predictive model to identify pregnancies at high risk of pre-eclampsia then observe the effect of a novel treatment (esomeprazole) on maternal blood pressure and the development of this disease.
Exploring And Targeting The Anti-Inflammatory Signalling Mechanisms Of Interleukin 37
Funder
National Health and Medical Research Council
Funding Amount
$1,018,306.00
Summary
Cytokines are messenger proteins that function as master regulators of biological processes; thus they play central roles in many diseases. The rare cytokines that block inflammation do so by dampening the immune system’s potentially destructive force, making them attractive targets for drug development. We showed that interleukin 37 is a powerful anti-inflammatory cytokine, and will now evaluate its mechanisms of action and its efficacy against several severe diseases, including cancer.
Innovative Antimicrobial Treatments For Successful Bone Allografts
Funder
National Health and Medical Research Council
Funding Amount
$473,706.00
Summary
Bone healing sites are commonly infected, and this is associated with adverse clinical and significant socioeconomic outcomes. These studies will determine whether our novel antimicrobials can be used to reduce bone infections by studying the combination of antimicrobials and bone in laboratory and bone fracture studies whilst minimising the potential of developing antibiotic resistance.
The outcomes to be assessed are recurrent ischaemic stroke, intracranial haemorrhage, myocardial infarction, parenchymal embolism and vascular death. Should these outcomes be significantly reduced, the public health and economic issues which will be addressed in this study are considerable. Approximately 40,000 new and recurrent cases of stroke occur in Australia each year, and about 80% of these are ischaemic. There is an average prevalence of about 20% of large or complex aortic plaque among p ....The outcomes to be assessed are recurrent ischaemic stroke, intracranial haemorrhage, myocardial infarction, parenchymal embolism and vascular death. Should these outcomes be significantly reduced, the public health and economic issues which will be addressed in this study are considerable. Approximately 40,000 new and recurrent cases of stroke occur in Australia each year, and about 80% of these are ischaemic. There is an average prevalence of about 20% of large or complex aortic plaque among patients with ischaemic stroke. About the same proportion of cases of ischaemic stroke yearly are associated with the presence of complex aortic plaque alone, and as many again with simple plaque (40% in total). Using the NHMRC estimated cost of $40,000 per stroke (and assuming that recurrent stroke costs are similar to initial stroke costs) and the estimated recurrent stroke rates of 11.9-100 person-years for plaque > 4 mm, the national cost of recurrent ischaemic stroke attributable to complex aortic plaque alone is about $3 million in the first year. This estimate does not include patients with incident TIA and atherosclerotic plaque or the resources spent on evaluating recurrent stroke and TIA attributable to aortic plaque, the cost of lost wages, or the negative impact on the quality of life of the victims. The economic and public health burden to our society could be greatly reduced by successful efforts at secondary stroke prevention in individuals with aortic plaque and TIA or ischaemic stroke. If just 25% of recurrent ischaemic strokes associated with aortic arch debris could be prevented by treatment interventions, the annual savings to society for recurrent ischaemic stroke alone would be considerable.Read moreRead less
Viral Infection And Transforming Growth Factor-beta Impair Glucocorticoid Activity In Epithelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$318,299.00
Summary
Anti-inflammatory types of steroid drugs are commonly used in chronic lung disease including asthma and chronic obstructive pulmonary disease. However, a significant number of sufferers show resistance to the steroid therapy. Our study is developing an understanding of how inflammation limits the anti-inflammatory effects of steroids and we are identifying novel therapeutic targets to improve the effectiveness of treatment of chronic disease.