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There is an unmet need for safe and effective anti-inflammatory drugs. Because P38 MAPK intracellular signalling modulates multiple pro-inflammatory cytokine actions, it appears to be an ideal candidate pathway. P38 inhibitors have been limited by their toxicity within hepatocytes. The aim of this program therefore is to develop agents with enhanced P38 MAPK inhibitory effects as well as reduced liver toxicity based on known structure activity relationships.
Protease Activated Receptor 2 Antagonist In Inflammatory Disease
Funder
National Health and Medical Research Council
Funding Amount
$621,347.00
Summary
The immune response to infection involves a network of proteins that produce an inflammatory response. Sometimes this response is prolonged or uncontrolled and can lead to a large number of inflammatory and other diseases. We have discovered a class of drugs that can bind to a particular protein on the surface of human cells and control this inflammatory response. This property has the potential to treat a wide range of inflammatory and other diseases in humans.
Mechanical Mobility Of The Thorax For Continuous Determination Of Lung Gas Volume
Funder
National Health and Medical Research Council
Funding Amount
$165,000.00
Summary
Percussion is a valuable clinical method for physical examination of parts of the body. A sharp tap (impulsive force) is applied to the body wall and the sound radiated in response is observed. This sound may be dull (over liver) or stony dull (pleural effusion), or resonant (over normal lung) or hyper-resonant (over bowel). While the variation in radiated sound is not fully understood, it is apparent that the presence of gas, which is highly compliant, increases mobility of the overlying tissue ....Percussion is a valuable clinical method for physical examination of parts of the body. A sharp tap (impulsive force) is applied to the body wall and the sound radiated in response is observed. This sound may be dull (over liver) or stony dull (pleural effusion), or resonant (over normal lung) or hyper-resonant (over bowel). While the variation in radiated sound is not fully understood, it is apparent that the presence of gas, which is highly compliant, increases mobility of the overlying tissue and allows it to resonate; where the sub-tissue is largely fluid, tissue mobility is low and the percussive sound is dull. Percussion is useful for examining the adult chest and lung, but cannot for example be applied in infant intensive care as only limited impulsive force can be used, and the adult finger, which is both a coupling device and sounding board, is too large. As well, percussion requires skill and quiet conditions. Accordingly, we developed a device to measure mobility of the chest and other tissues in real time. The VibroPulse applies a known low-level force to the body surface and records the resultant velocity induced in the surface. The force is generated by a vibrating mass set in motion by an electromagnetic motor driven by pseudo-random noise. Tissue mobility, defined as velocity-force, is derived simultaneously across the frequency range, providing an easily interpreted quantitative output unaffected by ambient noise. This proposal has two aims we can achieve in 1 year: (1) to continue evaluating VibroPulse sensitivity to tissue composition, using symmetrical percussive sites on the human chest and abdomen that are dull on one side and resonant on the other, and the chest of anaesthetised animals with experimentally induced pneumothorax and lung collapse, two life-threatening conditions for which percussion is a key diagnostic method, and (2) to engineer a small device from our bulky prototype that is suitable for clinical use, in infants and adults.Read moreRead less
Development Of A Vaccine For Genital Chlamydial Infection
Funder
National Health and Medical Research Council
Funding Amount
$207,551.00
Summary
Genital Chlamydia infections are the most common sexually transmitted infection in Australia with annual health costs of 90-160 million dollars. Infection rates in 15-29 olds are increasing at 15-20% per year. Antibiotics are currently the treatment of choice, however antibiotic resistance is increasing and most infections are asymptomatic and not treated in the absence of screening programs. This project aims to develop a genital Chlamydia vaccine using a combination of novel antigens.
Assessment Of Bilateral Oedema By Bioelectrical Impedance Analysis
Funder
National Health and Medical Research Council
Funding Amount
$180,000.00
Summary
Swelling of tissue due to fluid accumulation, known as oedema, is one of the earliest signs of diseases such as kidney failure, burn injury or lymphedema. All of these are not uncommon conditions. Lymphedema, for example, is a common sequela of radiotherapy or surgery in the treatment of malignancies such as breast, uterine, and prostatic carcinoma. It is reported to occur in up to 40% of patients depending on the type of surgery and whether or not the patient received radiotherapy. It is estima ....Swelling of tissue due to fluid accumulation, known as oedema, is one of the earliest signs of diseases such as kidney failure, burn injury or lymphedema. All of these are not uncommon conditions. Lymphedema, for example, is a common sequela of radiotherapy or surgery in the treatment of malignancies such as breast, uterine, and prostatic carcinoma. It is reported to occur in up to 40% of patients depending on the type of surgery and whether or not the patient received radiotherapy. It is estimated that at any time 100000 women are suffering from post- mastectomy lymphedema in Australia alone. Treatment of breast cancer alone therefore, given the incidence of the disease, produces a large at-risk population. Add to this other causes of oedema and the magnitude of the problem becomes clearly apparent. The presence of chronic oedema is often a disfiguring and disabling disorder, usually accompanied by pain, recurrent infection, reduced mobility and impaired function. In acute oedema the problem often resolves with recovery from the underlying pathology. In chronic oedema, progression may be arrested by early intervention including complex physical therapy (exercise regimen, compression bandaging, and massage) which is effective in reducing limb volume, in improving the quality of life, function and body image of patients. Although the assessment of oedema is clearly of clinical importance, relatively few objective and accurate techniques for its measurement exist. Research conducted over the past decade by the applicants has pioneered the Use of Bioelectrical Impedance Analysis for the assessment of lymphedema. This study aims to translate this basic research into clinical practice. Sensitivity and specificity studies will establish normative and threshold values for impedance measurements that can be used as presumptive indicators of oedema. User friendly technology and equipment suitable for clinical use will be developed which should improve treatment therapies.Read moreRead less
Development Of Recombinant RsolCD39-PSGL As A Novel Therapeutic With Anti-thrombotic And Anti-inflammatory Effects
Funder
National Health and Medical Research Council
Funding Amount
$186,367.00
Summary
Heart disease and stroke are due to a narrowing of arteries followed by occlusion, due a combination of clot formation initiated by platelet clumping, and inflammation surrounding the vessel wall. The currently available drugs are often limited by the adverse reaction of bleeding. We will investigate the efficiency of a new drug to prevent clot formation and inflammation.
Developing Anti-Inflammatory Drugs Based On Inhibition Of A Human Enzyme
Funder
National Health and Medical Research Council
Funding Amount
$160,000.00
Summary
Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachid ....Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachidonate, PAF, prostaglandins, leukotrienes, etc. there is a consensus that blockade of phospholipid metabolism would represent a major advance on NSAIDs as antiinflammatory agents. No sPLA2-IIa inhibitor is available yet in man. We aim to create an attractive data package showing proof of concept for a potent new type of antiinflammatory drug. This data will give us an improved negotiating position in our commercialisation of a new drug with potential multi-billion dollar markets as diverse as arthritis, asthma, reperfusion injury, organ transplantation and many other currently intractable human ailmentsRead moreRead less
Development And Biological Evaluation Of Cytokine Macrophage-migration Inhibitor (MIF) Non-Steroidal Antagonists
Funder
National Health and Medical Research Council
Funding Amount
$85,000.00
Summary
The cytokine macrophage-migration inhibitory factor (MIF) has a broad range of pro-inflammatory effects in the innate and adaptive immune system. CIA’s lab has demonstrated the potential importance of MIF in the pathology of chronic inflammation via studies in models of rheumatoid arthritis (RA). Similarly to other chronic inflammatory diseases, MIF is overexpressed in human RA, and induces activation of key pathological processes in RA cells. Moreover, antagonism of MIF with mAb profoundly inhi ....The cytokine macrophage-migration inhibitory factor (MIF) has a broad range of pro-inflammatory effects in the innate and adaptive immune system. CIA’s lab has demonstrated the potential importance of MIF in the pathology of chronic inflammation via studies in models of rheumatoid arthritis (RA). Similarly to other chronic inflammatory diseases, MIF is overexpressed in human RA, and induces activation of key pathological processes in RA cells. Moreover, antagonism of MIF with mAb profoundly inhibits models of RA and other inflammatory diseases, confirming MIF as a therapeutic target in human inflammatory disease. The X-ray crystal structure of MIF has been published and the putative active site fully characterised. We have deduced structural features of MIF that reveal aspects of the structural complementarity of host-guest affinity. This information has been used in the synthesis of new compounds to antagonise MIF. We have designed, synthesised and tested several classes of compounds, which have shown activity from milli to nano-molar levels in novel in-house in vitro bioassays.Read moreRead less
Commercialisation Of A Glycoprofiling Diagnostic Kit And Novel Therapies For Biofilm Related Respiratory Disorders
Funder
National Health and Medical Research Council
Funding Amount
$203,050.00
Summary
Our preliminary studies have shown that a group of patients who suffer from chronic inflammatory disease and have bacterial biofilm identified on their mucosa have worse outcomes even after surgery. We have shown that they lack certain small protein and sugar molecules on their respiratory lining. We aim to use this technology as a diagnostic tool to aid the doctor in prescribing the appropriate treatment for these patients to prevent bacteria regrowing in their respiratory tract.