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
Novel Strategies To Boost Tristetraprolin Function: A Critical Anti-inflammatory Protein In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$547,216.00
Summary
Asthma is a chronic disorder where airways are remodelled, resulting in poor lung function. Airway remodelling is a consequence of long-term inflammation. As current treatments halt some, but not all, aspects of airway remodelling, new therapeutic approaches are urgently required. In this grant, our aim is to devise novel strategies to boost the function of a critical anti-inflammatory protein - TTP - to reduce inflammation in asthma.
Inflammation And Oxidative Stress In Emerging Psychotic And Mood Disorders
Funder
National Health and Medical Research Council
Funding Amount
$432,619.00
Summary
We are conducting four large clinical trials testing anti-inflammatory treatments like ?-3 PUFAs and aspirin in young people who are at high-risk for psychosis or have depression. This proposal adds an important component to this research by investigating inflammatory and oxidative stress markers. We aim to determine if the investigated biomarkers predict the course of illness and response to treatments. The findings will facilitate early intervention and targeted treatment.
During injury or infection, our body’s immune system protects us by launching inflammation. But uncontrolled inflammation drives common diseases such as cancer, diabetes, Alzheimer’s and Parkinson's. This research program will reveal how the body deactivates inflammasomes – protein complexes at the heart of inflammation and disease – so we can design better drugs for treating patients with inflammation-driven disease.
During injury or infection, our body’s immune system protects us by launching inflammation. But uncontrolled inflammation drives common diseases such as cancer, diabetes and Alzheimer’s. This project will reveal how the body deactivates inflammasomes - protein complexes at the heart of inflammation and disease – so we can design better strategies for treating patients with inflammation-driven disease.
A-Prof Roberst is a clinical haematologist caring for patients with blood cancers, who is committed to developing new therapies for currently incurable diseases through laboratory and clinical trial research.
Design And Evaluation Of Inhibitors Of Phospholipases A2 As Anti-Inflammatory Drugs
Funder
National Health and Medical Research Council
Funding Amount
$317,545.00
Summary
There are at least 16 types of enzymes called phospholipases A2 (PLA2). They are found in venoms of snakes, bees, lizards, cone snails, etc and act as toxic and digestive agents. PLA2 enzymes are also found in cells and tissues of mammals where they carry out a wide range of digestive, maintenance, immune defence, and cell signalling functions. The human pancreas secretes one form of PLA2 into the gut to aid digestion. Human immune cells (macrophages, thymocytes, spleen leukocytes, platelets) us ....There are at least 16 types of enzymes called phospholipases A2 (PLA2). They are found in venoms of snakes, bees, lizards, cone snails, etc and act as toxic and digestive agents. PLA2 enzymes are also found in cells and tissues of mammals where they carry out a wide range of digestive, maintenance, immune defence, and cell signalling functions. The human pancreas secretes one form of PLA2 into the gut to aid digestion. Human immune cells (macrophages, thymocytes, spleen leukocytes, platelets) use other forms of PLA2 in the inflammatory immune response to kill infectious foreign agents like viruses and bacteria. One form of PLA2, known as type IIa, is the main bacteria-killing ingredient of human tears and it is also a chief component of fluid from the joints of patients with arthritis. Type IIa PLA2 is present in abnormally high levels in blood from humans with arthritis, burns, sepsis, ARDS, atherosclerosis, Crohn's disease, malaria, cancer and other chronic illnesses. These high levels can cause injury, tissue damage and pain due to too much inflammation and treatments are needed to stop or decrease effects of this enzyme . For these reasons this and related enzymes are thought to be potential targets for drugs which would act by blocking the functions of such an enzyme. Our group has been using computers to design new chemicals that can selectively fit into this enzyme and stick very tightly. We are determining the three dimensional structures of these chemicals in the enzyme to learn how to make them bind even more tightly. This information is allowing us to synthesize new selective drugs that stop PLA2 from promoting the development of disease. We propose to continue these studies towards developing powerful new antiinflammatory drugs that block the enzyme, and to demonstrate possible benefits of these drugs by testing them in animal models of arthritis, sepsis, adult respiratory distress syndrome (ARDS), period pain, malaria, and cancer.Read moreRead less
Resolvin E1 Is A Novel Anti-inflammatory And Anti-fibrotic Lipid Mediator For The Treatment Of Chronic Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$519,246.00
Summary
This project will ascertain whether a naturally occurring compound, Resolvin E1 with potent anti-inflammatory properties, can effectively halt the progression of experimental kidney disease. We will also test whether Resolvin E1 can exert other potential benefits in suppressing progressive fibrosis of the kidney. The outcome of this study will allow us to evaluate the therapeutical potential of Resolvin E1 for the treatment of acute and chronic kidney diseases.
The Mechanism Of Action Of Secreted Phospholipase A2 And Its Inhibition In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$554,400.00
Summary
Secretory phospholipase A2 (sPLA2) is an important mediator of inflammation and is clinically associated with the onset and severity of several immune-mediated diseases including arthritis, asthma, atherosclerosis, psoriasis and recently prostate cancer. These are complex diseases which are poorly understood. We have shown that sPLA2 can by itself and in combination with inflammatory cytokines modulate signalling pathways in cells derived from the joints of patients with arthritis to upregulate ....Secretory phospholipase A2 (sPLA2) is an important mediator of inflammation and is clinically associated with the onset and severity of several immune-mediated diseases including arthritis, asthma, atherosclerosis, psoriasis and recently prostate cancer. These are complex diseases which are poorly understood. We have shown that sPLA2 can by itself and in combination with inflammatory cytokines modulate signalling pathways in cells derived from the joints of patients with arthritis to upregulate inflammatory molecules. How this happens is completely unknown. We plan to work out how this enzyme does this. We have also developed small cyclic peptide inhibitors of sPLA2 which potently block the function of the enzyme in these cells. We plan to determine how this happens and if these inhibitors are effective at blocking inflammation and arthritis. The proposal may identify new mechanisms by which secreted factors upregulate inflammation in human cells and may lead to the discovery of new ways to intervene to block these pathways.Read moreRead less