Regulation Of Lysosomal Proteases By The Intracellular Serpin, PI-6.
Funder
National Health and Medical Research Council
Funding Amount
$152,500.00
Summary
All cells have a graded response to stress. At low levels of stress, intrinsic systems counter the stressor and repair damage. As stress increases and irreparable damage is likely, affected cells suicide in a pre-programmed manner, and are rapidly engulfed by their neighbours to prevent initiation of a deleterious inflammatory response. Finally, if subjected to overwhelming stress, cells may burst and trigger an inflammatory response. Emerging evidence shows that several organelles in the cell a ....All cells have a graded response to stress. At low levels of stress, intrinsic systems counter the stressor and repair damage. As stress increases and irreparable damage is likely, affected cells suicide in a pre-programmed manner, and are rapidly engulfed by their neighbours to prevent initiation of a deleterious inflammatory response. Finally, if subjected to overwhelming stress, cells may burst and trigger an inflammatory response. Emerging evidence shows that several organelles in the cell act as stress sensors and participate in initiating programmed cell death. In particular, it appears that degradative enzymes (proteases) released under stress from waste disposal-recycling organelles (lysosomes) can induce death. This may occur in settings such as infection or cardiovascular disease (e.g. stroke). As part of a defence mechanism to counter low level release of these lysosomal proteases, we propose that some cells produce inhibitors called serpins. In preliminary work we have shown that particular serpins do indeed inactivate a subset lysosomal proteases. We propose to study the role of these serpins in protecting cultured cells from stress and the effects of lysosomal protease release. In addition, we will use mice lacking one of these serpins to evaluate its importance in the physiological response to stresses such as bacterial and viral infection, tumor formation and stroke.Read moreRead less
I am an immunochemist-cell biologist investigating the involvement endosomes and lysosomes in different disease states. A primary focus has been on the group of diseases called lysosomal storage disorders where early diagnostic and effective treatment strategies have been and continue to be developed. Due to the multi-functionality of endosomes and lysosomes, these critical organelles are also involved in the pathology caused by other major diseases like bacterial infection and cancer, and this ....I am an immunochemist-cell biologist investigating the involvement endosomes and lysosomes in different disease states. A primary focus has been on the group of diseases called lysosomal storage disorders where early diagnostic and effective treatment strategies have been and continue to be developed. Due to the multi-functionality of endosomes and lysosomes, these critical organelles are also involved in the pathology caused by other major diseases like bacterial infection and cancer, and this is being actively investigated.Read moreRead less
Treatment Of Lysosomal Storage Disorder Patients By Drug-enhanced Premature Stop Codon Read-through
Funder
National Health and Medical Research Council
Funding Amount
$431,764.00
Summary
Lysosomal storage disorders are a devastating set of genetic diseases with very severe clinical symptoms. In this project, we will investigate a new treatment strategy that is non-invasive and that will be applicable for a wide range of lysosomal storage disorder patients. The therapy will over-ride the molecular genetic lesion and will be preferentially targeted for patients who are at the severe end of the clinical spectrum, where treatment options are currently limited.
Evaluation And Comparison Of Lentiviral And AAV Vector Mediated Gene Therapy For The Mucopolysaccharidoses
Funder
National Health and Medical Research Council
Funding Amount
$521,320.00
Summary
The mucopolysaccharidoses are a group of inherited diseases that have profound consequences for affected individuals. They have pleiotropic effects and usually result in premature death. Although intravenous enzyme replacement therapy has been developed for a number of these disorders, this approach to therapy is invasive, very expensive, of limited efficacy, and is completely ineffective in treating brain pathology. The principal reason for this is the protected nature of the brain which preven ....The mucopolysaccharidoses are a group of inherited diseases that have profound consequences for affected individuals. They have pleiotropic effects and usually result in premature death. Although intravenous enzyme replacement therapy has been developed for a number of these disorders, this approach to therapy is invasive, very expensive, of limited efficacy, and is completely ineffective in treating brain pathology. The principal reason for this is the protected nature of the brain which prevents enzymes that are administered intravenously from entering. Therefore, alternative therapies must be considered in order to provide more effective therapy for the mucopolysaccharidoses, especially those that have significant brain pathology. Gene therapy is one such alternative therapy but this still faces the problem of introducing the therapeutic agent (in this case the gene encoding the requisite enzyme) into the brain. This project aims to provide a comparitive evaluation of two gene therapy vectors for their efficacy in treating all aspects of the pathology found in the mucopolysaccharidoses. Both vectors have the properties of being able to efficiently deliver genes to different cell types and result in the stable genetic modification of the target cell, making them ideal for long-term treatment. However, for effective gene therapy, significant and widely distributed gene delivery to the brain, as well as to other tissues, will be required. This project aims to compare the efficacy of these vectors in two different animal models of the mucopolysaccharidoses that exhibit a wide range of the clinical problems associated with these diseases, importantly including brain pathology.Read moreRead less
Is The Eye A Window To The Brain In Sanfilippo Syndrome?
Funder
National Health and Medical Research Council
Funding Amount
$852,967.00
Summary
Study of the retina and optic nerve permits evaluation of central nervous system – these structures contain both neurons and glia and are outgrowths of the developing brain. Therefore, eye examination may allow us to study the brain and monitor brain disease and the effect of therapy. This project will determine whether brain disease in a childhood-onset disorder (Sanfilippo syndrome) and treatment of it, can be monitored in this way.
PROTEIN PROFILING FOR THE IDENTIFICATION AND MONITORING OF LYSOSOMAL STORAGE DISORDERS AND OTHER NEUROLOGICAL DISEASES
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Lysosomal storage disorders (LSD) are a group of more than 45 progressive genetic diseases, that result from the absence or impaired function of a specific enzyme in each of the body's cells. Lysosomes rid the cell of excess waste. Impaired enzyme function halts this process and waste begins to accumulate (or 'store') in the cell. Disease severity and patient longevity is variable, but severely affected patients often die by their mid-teens. LSD can affect the skeleton and joints, respiratory an ....Lysosomal storage disorders (LSD) are a group of more than 45 progressive genetic diseases, that result from the absence or impaired function of a specific enzyme in each of the body's cells. Lysosomes rid the cell of excess waste. Impaired enzyme function halts this process and waste begins to accumulate (or 'store') in the cell. Disease severity and patient longevity is variable, but severely affected patients often die by their mid-teens. LSD can affect the skeleton and joints, respiratory and cardiovascular systems, the brain, the eyes, the ears and the airways. As affected children become older, symptoms worsen. Patients often require frequent hospitalisation, and medical and surgical intervention. Approximately 10 to 15% of the general population are affected or carriers of an LSD. In Australia, one LSD child is born in every 5,000 live births. Diagnosis often takes several years, and families often have other children before their affected child is diagnosed. LSD are, therefore, a considerable burden to not only the families but also to the health care system. The goal of the Lysosomal Diseases Research Unit is Diagnosis at birth and effective therapy for lysosomal storage disorders. To this end we have been working toward the development of a newborn screening program for LSD and improved methods for the diagnosis and monitoring of therapy in this group of diseases. In this project we propose to develop and evaluate the use of protein profiling (looking at many diagnostic markers at the same time) to achieve these goals. The technology developed in this project will have potential application beyond LSD. Lysosomal dysfunction has been implicated in Alzheimer's disease and Parkinson's disease; in addition lysosomal proteins are reported to be involved in the spread of some cancers and may be useful markers for early detection. We will collaborate with other research groups to further develop protein profiling in these areas.Read moreRead less
Proteinase Inhibitor 6: A Multifunctional Intracellular Serpin
Funder
National Health and Medical Research Council
Funding Amount
$217,435.00
Summary
We have discovered and characterized an unusual protease inhibitor that is widely distributed in the body. We have shown that the inhibitor is present in immune cells that are responsible for fighting bacterial infection, and that its role is probably to protect these cells against a powerful endogenous protease produced to destroy ingested bacteria. The inhibitor probably has additonal roles because it is present in developing and adult brain, skin and other blood cells. In these tissues we hav ....We have discovered and characterized an unusual protease inhibitor that is widely distributed in the body. We have shown that the inhibitor is present in immune cells that are responsible for fighting bacterial infection, and that its role is probably to protect these cells against a powerful endogenous protease produced to destroy ingested bacteria. The inhibitor probably has additonal roles because it is present in developing and adult brain, skin and other blood cells. In these tissues we have evidence that inhibitor regulates other, unidentified, proteases. The purpose of this grant is to identify these proteases, and to elucidate the physiological significance of the inhibitor by studying mice that lack it.Read moreRead less