Proteolytic Processing Of Alzheimer's Amyloid Precursor: Identification Of Gamma-secretase
Funder
National Health and Medical Research Council
Funding Amount
$240,581.00
Summary
Alzheimer's disease is the major cause of dementia among the elderly and affects more than 20% of the population aged 80 and over. There is no cure for the disease and the treatments currently available can only retard its progression and have serious side-effects. Examination of the brain from subjects who died from Alzheimer's disease shows lesions: these are called amyloid plaques. The plaques are formed by the abnormal accumulation of an insoluble and toxic protein which causes death of the ....Alzheimer's disease is the major cause of dementia among the elderly and affects more than 20% of the population aged 80 and over. There is no cure for the disease and the treatments currently available can only retard its progression and have serious side-effects. Examination of the brain from subjects who died from Alzheimer's disease shows lesions: these are called amyloid plaques. The plaques are formed by the abnormal accumulation of an insoluble and toxic protein which causes death of the brain cells. Some gene defects which cause Alzheimer's disease at an early age (30-60 years) are known to accelerate the accumulation of the toxic protein, thereby causing progressive degeneration of the brain. Our research is aimed at understanding at the molecular level how the toxic protein forms. We know that it is part of a large protein and that its release requires two enzyme cuts. Now we propose to isolate and characterize these enzymes and to search for drugs which will neutralize them. This constitutes a rational approach to a therapeutic strategy fo halting or slowing down the progression of Alzheimer's disease.Read moreRead less
Proteases, Their Inhibitors And Receptors In Degenerative Disease
Funder
National Health and Medical Research Council
Funding Amount
$5,843,388.00
Summary
Many of the themes of this program are aimed at understanding the molecular basis of several important degenerative diseases that in particular affect the ageing population. These include osteoporosis, arthritis, periodontal disease, wasting diseases of muscle and inherited disorders such as antitrypsin deficiency. The five CI’s on this application have formed a collaborative network since 1996. Dr Whisstock is a bioinformatician and structural biologist with a research focus on the serpin super ....Many of the themes of this program are aimed at understanding the molecular basis of several important degenerative diseases that in particular affect the ageing population. These include osteoporosis, arthritis, periodontal disease, wasting diseases of muscle and inherited disorders such as antitrypsin deficiency. The five CI’s on this application have formed a collaborative network since 1996. Dr Whisstock is a bioinformatician and structural biologist with a research focus on the serpin superfamily of protease inhibitors and their protease partners. He is currently the scientific director of the Victorian Bioinformatics Consortium and an NHMRC Senior Research Fellow. Dr Bird is an NHMRC Senior Research Fellow who discovered the intracellular branch of the serpin superfamily and formulated the hypothesis that describes their function. A-Prof Mackie is a world expert in the field of musculoskeletal biology and pathology. Dr Bottomley is a Senior Logan Fellow and RD Wright Fellow whose research focuses upon how proteins misfold and lead to disease. Dr Pike is an enzymologist whose research area encompasses a wide range of bacterial and mammalian proteases involved in the pathology of human disease. Each individual in this team brings different skills which makes this a very important and powerful collaboration. The research is extensive and involves protein folding, enzyme kinetics, molecular modelling, structural biology, bioinformatics, cell biology and pathology, enzyme kinetics and drug design. Collectively the CI’s have a total of 154 papers since 1998, of which a third include two or more of the CI’s as co-authors. Currently the team holds over >$5 million in grant funding. The team is augmented by four P.I.s: Dr Buckle is a talented structural biologist; Dr Scott is a molecular cell biologist who holds an NHMRC CJ Martin Fellow; Dr Garcia de la Banda is a computer scientist based at Monash and Dr Grigoryev is a world expert in chromatin condensation based at Penn State University (USA).Read moreRead less
Role Of Neutrophil Proteases And Their Inhibitors In Haematopoietic Stem Cell Mobilisation
Funder
National Health and Medical Research Council
Funding Amount
$472,750.00
Summary
Mobilisation is the enforced migration of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent used to induce mobilisation of haemopoietic stem cells is a cytokine called G-CSF. In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow aspirates. The simplicity of the procedure (daily injections of G-CSF, absence of bone marrow aspiration) ....Mobilisation is the enforced migration of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent used to induce mobilisation of haemopoietic stem cells is a cytokine called G-CSF. In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow aspirates. The simplicity of the procedure (daily injections of G-CSF, absence of bone marrow aspiration), better patient recovery and survival, lower costs have all contributed to the success of this procedure. Despite its common use in clinics to rescue cancer patients undergoing high-dose chemotherapy, the reasons why haemopoietic stem cells mobilise are still not fully understood. It is known that haemopoietic stem cells stay in the bone marrow because they express 'adhesive' molecules on their surface. In pioneering work, this laboratory has shown that cytokines such as G-CSF increases the number of neutrophils (a type of white blood cell) in the bone marrow. These neutrophils release enzymes (known as proteases) which cut into pieces the 'adhesive' molecules and other proteins responsible for the retention of blood forming cells within the bone marrow. This project aims to further these investigations to include both the role of proteases and their naturally-occurring inhibitors in the mobilisation of blood forming cells. Particularly, we will investigate how the expression of serpins and TIMPs, two families of protease inhibitors, is regulated in the bone marrow during mobilisation and how these inhibitors control the activity of proteases responsible for the mobilisation of blood forming cells. This knowledge may lead to the design of new treatments that induce more efficient mobilisation and ultimately improve the success of haemopoietic stem cell transplantation.Read moreRead less
Kallikrein Proteases Have Key Functional Roles In Peritoneal Invasion And Chemoresistance In Epithelial Ovarian Cancer
Funder
National Health and Medical Research Council
Funding Amount
$815,541.00
Summary
Only 30% of ovarian cancer patients with advanced disease survive for 5 years. This is because the cancer quickly spreads into the abdominal cavity and often becomes resistant to chemotherapy. We aim to use a new 3D culture system, mouse models and novel inhibitors to study the roles of 4 kallikrein enzymes in these events. The outcomes from this study will lead to a better understanding of the role of kallikreins in ovarian cancer and may lead to new treatment approaches.
Control Of Mast Cell Tryptase Function In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$302,627.00
Summary
Allergic disorders such as anaphylaxis, eczema, hay fever and asthma affect about 25% of the developed world. Australia has one of the highest asthma prevalence in the world, costing Australians about a billion dollars a year. One of the central players in allergies is the mast cell enzyme, ?-tryptase. We have discovered a new mechanism of control of this enzyme. This research will aid the development of specific and potent inhibitors of ?-tryptase for the treatment of allergic disorders.