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Novel Approaches To Pathogenesis, Diagnosis &treatment Of Autoimmune Diseases Based On New Insights Into Thymus-dependen
Funder
National Health and Medical Research Council
Funding Amount
$1,045,422.00
Summary
An individual relies upon their immune system to protect against invasion by hostile organisms. The system usually works well. Invading agents (the 'non-self') are detected and attacked by the immune system's patrolling killer T cells. These normally beneficial cells are called T cells because they were formed and educated in an organ called the thymus, which kick-starts our immune system in childhood, but falls into inactivity by adolescence. Sometimes the education system in the thymus goes wr ....An individual relies upon their immune system to protect against invasion by hostile organisms. The system usually works well. Invading agents (the 'non-self') are detected and attacked by the immune system's patrolling killer T cells. These normally beneficial cells are called T cells because they were formed and educated in an organ called the thymus, which kick-starts our immune system in childhood, but falls into inactivity by adolescence. Sometimes the education system in the thymus goes wrong and it releases T cells that mistakenly attack 'self' instead of 'non-self'. This causes autoimmune diseases, such as type1 diabetes, multiple sclerosis and rheumatoid arthritis. The Euro-Thymaide project aims to determine why and how self-attacking T cells are mistakenly released from the thymus into the body. Usually such errant T cells are detected and destroyed within the thymus, before they have the opportunity to escape and cause autoimmune diseases. The ultimate objective is to learn about the thymus recognition process and help the immune system detect and destroy faulty T cells that patrol the body, thereby preventing the onset of autoimmune diseases.Read moreRead less
In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune syste ....In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune system and to test ways of protecting beta cells from these mechanisms. Because of the inaccessibility of the pancreas to study (particularly biopsy) in humans with diabetes, much of the proposed work will be carried out in b cells derived from non-obese diabetic (NOD) mice, the best available mouse model of type 1 diabetes. It is clear from the literature that a molecule called perforin found in cytoxic T lymphocytes (CTL) is a major, if not the major, mechanism the immune system uses against b cells. For this reason we will try to better understand the interaction between b cells and perforin and ultimately design ways of them from perforin-mediated cell death. It is equally clear that there are other mechanisms besides perforin that can cause b cell death and the program will also address discovery of these mechanisms and new ways to block them. Beta cells in NOD mice will be protected from perforin or other mechanisms by the addition of protective genes or removal of harmful genes using transgenic knockout technology. Addition or removal of genes involved in cell death can be done systematically and each protocol tested using NOD mouse model. The process of cell death that b cell undergo in type 1 diabetes is called apoptosis. Apoptosis is a general mechanism by which cells of all types die. Experts in the biology of apoptosis and perforin are important members of the program, providing the opportunity to translate the latest advances in cell death research to diabetes. This research addresses several of the specific research areas of interest to JDRF. It focuses on the prevention of b cell death in individuals with type 1 diabetes receiving islet transplants. It may be applicable in the future to protection of stem or precursor cells that have been differentiated into b cells or even to devising strategies to prevent the development of diabetes.Read moreRead less
Role Of Heparan Sulfate, Heparanase Inhibitors In The Development And Prevention Of Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$3,242,772.00
Summary
Our recent studies have shown that a special protein (an enzyme called heparanase) and the special carbohydrate (heparan sulfate or HS) that it degrades, play a previously unrecognised role in the development of Type I diabetes (T1D) in mice. We will explore whether destructive immune cells use heparanase to damage insulin-producing islets and deplete them of HS, resulting in islet cell death and T1D. We will develop new agents to inhibit this damage, prevent T1D and protect islet transplants.
The principle objective of the proposed project is to determine the molecular, cellular extracellular matrix pathology of chondrodysplasia phenotypes which result from mutations in a variety of different gene products that are important for normal bone development. To achieve our objective the Eurogrow consortium has developed an extensive series of mouse models of chondrodysplasias that closely mimic the relevant human phenotype. The consortium will use a multidisciplinary systems biology appro ....The principle objective of the proposed project is to determine the molecular, cellular extracellular matrix pathology of chondrodysplasia phenotypes which result from mutations in a variety of different gene products that are important for normal bone development. To achieve our objective the Eurogrow consortium has developed an extensive series of mouse models of chondrodysplasias that closely mimic the relevant human phenotype. The consortium will use a multidisciplinary systems biology approach to determine the molecular mechanisms that underpin the pathophysiology of these distinct chondrodysplasias. From this approach we can expect to identify common disease mechanisms and learn general principles about genotype-phenotype correlations in chondrodysplasia phenotypes. The NHMRC-EU grant is to fund a consortium (Eurogrow) of 10 EU research groups (led by the University of Manchester) along with my research group at the MCRI to conduct these integrated studies.Read moreRead less
Neonatal Immunization With Pneumococcal Conjugate Vaccine In Papua New Guinea
Funder
National Health and Medical Research Council
Funding Amount
$1,181,966.00
Summary
One million children die every year of pneumococcal (Pnc) disease, the majority in the third world. Many die in early infancy and babies may benefit from immunisation with a Pnc conjugate vaccine (PrevenarTM) at birth. The Papua New Guinea (PNG) Insatiate of Medical Research; Telethon Institute for Child Health Research and the Department of Paediatrics, University of Western Australia, will collaborate to closely examine the safety of this approach, particularly with regard to impact on the dev ....One million children die every year of pneumococcal (Pnc) disease, the majority in the third world. Many die in early infancy and babies may benefit from immunisation with a Pnc conjugate vaccine (PrevenarTM) at birth. The Papua New Guinea (PNG) Insatiate of Medical Research; Telethon Institute for Child Health Research and the Department of Paediatrics, University of Western Australia, will collaborate to closely examine the safety of this approach, particularly with regard to impact on the development of immunity and response to other vaccines given to infants. This study will also provide a unique opportunity for training of PNG and Australian scientists in both countries; transfer state-of-the-art immunological technology and stimulate further collaborations on respiratory infections in the region.Read moreRead less
Assessment Of The Effectiveness Of Australian Models Of Palliative Care Delivery In Four Neurodegenerative Disorders
Funder
National Health and Medical Research Council
Funding Amount
$150,000.00
Summary
This study will be conducted in three Australian states (Queensland, Victoria and West Australia), to assess the effectiveness of existing palliative care service delivery to people with motor neurone disease, multiple sclerosis, Huntington’s disease or Parkinson’s disease, and to their families. In phase I, interviews will be conducted with people who have these diseases, their families, and health professionals to discover the needs for palliative care services. In phase II, a survey will dete ....This study will be conducted in three Australian states (Queensland, Victoria and West Australia), to assess the effectiveness of existing palliative care service delivery to people with motor neurone disease, multiple sclerosis, Huntington’s disease or Parkinson’s disease, and to their families. In phase I, interviews will be conducted with people who have these diseases, their families, and health professionals to discover the needs for palliative care services. In phase II, a survey will determine the extent to which these needs are met. The findings will be used to recommend improved palliative care delivery models.Read moreRead less
Production Of Nasal Filters: Enhanced Prophylactic Protection From Aerosol Exposure
Funder
National Health and Medical Research Council
Funding Amount
$147,000.00
Summary
Influenza is a highly contagious disease that is transmitted via infective secretions containing the virus. An infected person produces tiny droplets of these secretions when coughing, sneezing, and talking, and the droplets are disseminated into the air where they are subsequently inhaled by others. A common way of preventing such transmission is to wear a mask to prevent droplet inhalation. While such masks may greatly reduce exposure, they do not eliminate it, as some viruses can pass around ....Influenza is a highly contagious disease that is transmitted via infective secretions containing the virus. An infected person produces tiny droplets of these secretions when coughing, sneezing, and talking, and the droplets are disseminated into the air where they are subsequently inhaled by others. A common way of preventing such transmission is to wear a mask to prevent droplet inhalation. While such masks may greatly reduce exposure, they do not eliminate it, as some viruses can pass around the edges of masks, particularly if it fits poorly, and also a small percentage can pass through the filter material. While influenza is usually not a major health problem in the general community, the emergence of a more hazardous strain will place an additional burden on health care and other facilities, and requires the development and optimization of measures to minimize virus spread and protect those who are exposed. The aim of this project is to build small filters that can be worn in the nose to provide additional filtration of inhaled air. These filters would be worn in combination with a mask in high exposure circumstances, such as by health care workers when treating infected patients or could be used when a mask was not normally worn to provide effective and discreet protection, such as in crowded public places. Developing such filters builds on our experience of making small samplers worn in the nose to measure allergen exposure. This experience is combined with advanced filter materials developed by leading US researchers that permit the efficient filtration of particles as small as viruses. This project will be conducted in collaboration with a leading Australian design group, and we will design and evaluate such filters for their ability to capture virus and thus protect the wearer. The filters should provide an intuitive, effective and inexpensive method to be used in combination with other hygiene measures to increase personal protection from acquiring highly transmissible respiratory diseases, particularly influenza. We expect to have prototypes of the filters available in 6 months so that production can commence.Read moreRead less
Genome-wide Combined Linkage-association Scan Of Multiply Phenotyped Twin Sibships
Funder
National Health and Medical Research Council
Funding Amount
$1,920,000.00
Summary
We have a large ongoing study of adolescent twins, their siblings and parents who are multiply phenotyped in many domains including melanoma risk factors, serum biochemistry, and cognition. We used our first Medical Genomics grant to obtain a 5cM linkage scan for>500 families and have identified linkage peaks for many different phenotypes. To fine map these it will be most efficient to carry out a genome-wide association scan. We request funds to type a 500k SNP chip on 1000 individuals.
Measuring Changes In Fluids, Fat, Muscle Mass, Proteins & Other Body Components Non-invasively Through Course Of Illness
Funder
National Health and Medical Research Council
Funding Amount
$120,000.00
Summary
The course of non-cancer related disease is difficult to assess clinically making it hard for clinicians to accurately predict the end of life course of illness for patients. No matter what the end of life disease is, death will involve multi-system organ failure and changes in body composition. These changes, including fluid distribution, muscle mass and type and fat mass as well as measures of body mass index, basal metabolic rate and arm muscle circumference can be accurately followed with no ....The course of non-cancer related disease is difficult to assess clinically making it hard for clinicians to accurately predict the end of life course of illness for patients. No matter what the end of life disease is, death will involve multi-system organ failure and changes in body composition. These changes, including fluid distribution, muscle mass and type and fat mass as well as measures of body mass index, basal metabolic rate and arm muscle circumference can be accurately followed with non-invasive multi-frequency bio-impedance. This information will provide a basis to either confirm the clinical diagnosis or lead to recommendations for change.Read moreRead less