GENETIC FACTORS AND REGIONAL BRAIN ATROPHY IN THE DIAGNOSIS OF DEMENTIA WITH LEWY BODIES
Funder
National Health and Medical Research Council
Funding Amount
$605,151.00
Summary
The number of people with dementia is increasing in Australia as people live longer. Dementia sometimes has a genetic basis and identification of such cases has improved our understanding of the events leading to the destruction of the brain tissue. In the vast majority of people, the degenerative changes were previously thought to be as a result of Alzheimer's disease. However, our recent research, funded by the NHMRC, confirms international findings showing more than 25% of people with dementi ....The number of people with dementia is increasing in Australia as people live longer. Dementia sometimes has a genetic basis and identification of such cases has improved our understanding of the events leading to the destruction of the brain tissue. In the vast majority of people, the degenerative changes were previously thought to be as a result of Alzheimer's disease. However, our recent research, funded by the NHMRC, confirms international findings showing more than 25% of people with dementia have a different disease called Dementia with Lewy bodies or DLB. Of course identifying these patients occurs at death when the cells in the brain can be examined for Lewy bodies. We now know that the brain degeneration differs significantly in patients with this disease. However, it is still not possible to identify DLB in life with any certainty. This project aims to develop objective methods to clinically differentiate dementia patients. We will seek out families in which genetic influences may underly the disease and determine whether these factors differ from those found in other dementing illnesses. Also, our preliminary studies have observed volume loss in a particular brain region in pathologically confirmed DLB patients. We wish to do further measurements to determine if tissue loss in this region can clinically differentiate DLB patients. In addition, we will determine the reasons for the tissue loss by careful pathological studies.Read moreRead less
Nutrient And Hormone Delivery To Muscle: Interactions Between Insulin And Exercise
Funder
National Health and Medical Research Council
Funding Amount
$304,375.00
Summary
Exercise is known to be beneficial in the treatment and prevention of Type 2 diabetes and in particular muscle insulin resistance. Also, exercise and insulin share similar acute actions on muscle. Firstly, muscle contraction has a well established action to increase glucose uptake, and secondly, both muscle contraction and insulin act to increase capillary recruitment. This latter phenomenon is thought to enhance nutrient delivery and waste product removal. There is evidence that the increase in ....Exercise is known to be beneficial in the treatment and prevention of Type 2 diabetes and in particular muscle insulin resistance. Also, exercise and insulin share similar acute actions on muscle. Firstly, muscle contraction has a well established action to increase glucose uptake, and secondly, both muscle contraction and insulin act to increase capillary recruitment. This latter phenomenon is thought to enhance nutrient delivery and waste product removal. There is evidence that the increase in capillary flow due to muscle contraction is accompanied by increases in total blood flow. For insulin action we now have preliminary data to indicate that capillary recruitment occurs within a 5-10 min application of a physiologic dose of insulin independent of a change in total blood flow suggesting a redistribution of flow. Muscle contraction also increases capillary recruitment and it raises the question of whether similar mechanisms underlie insulin- and muscle contraction-induced capillary recruitment or whether there are distinct and complementary pathways. In this project we plan to define the mechanisms responsible for contraction- and insulin-induced capillary recruitment in muscle. We hypothesize that similar mechanisms are operative, with both insulin and muscle contractions acting via NO-dependent mechanisms. Because of capillary reserve, and different initial steps of the signalling systems stimulated by insulin and exercise, capillary recruitment by combined contraction and insulin stimuli will be additive at both sub maximal and perhaps at maximal insulin pathway stimulation. Signalling mechanisms will be compared and the role of non-nutritive route as a flow reserve assessed.Read moreRead less
Role Of Adhesion Molecules In Autoimmune Vasculitis
Funder
National Health and Medical Research Council
Funding Amount
$377,036.00
Summary
Lupus is a disease which causes inflammation and pain throughout the body. The inflammation is caused by white blood cells attacking the lining of blood vessels in tissues. The aim of this project is to understand the reasons why these white blood cells attack the blood vessel lining. This process is impossible to study in humans. However, there is a strain of mouse which is affected by a disease which is very similar to human lupus. This disease occurs spontaneously in these mice. Using a micro ....Lupus is a disease which causes inflammation and pain throughout the body. The inflammation is caused by white blood cells attacking the lining of blood vessels in tissues. The aim of this project is to understand the reasons why these white blood cells attack the blood vessel lining. This process is impossible to study in humans. However, there is a strain of mouse which is affected by a disease which is very similar to human lupus. This disease occurs spontaneously in these mice. Using a microscope, it is possible to study the tiny blood vessels which are affected by this disease in these mice . Under the microscope, it is possible to see the white blood cells as they undergo the process of attacking the blood vessel lining. Visualizing this attack then allows us to study it and determine which molecules are important in causing this damaging inflammatory response. Specifically I will examine diseased blood vessels in the skin and brain of these mice, two of the tissues most dramatically affected by this disease. This information should help us gain an increased understanding of lupus as it affects humans.Read moreRead less
Factors Controlling Leucocyte Migration In Healthy Intestine And In Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$195,217.00
Summary
Inflammatory bowel diseases (IBD) are relapsing and remitting disorders of the intestine that create substantial disability in a relatively young population of patients. Our treatments for these conditions have changed little in the last 30 years and they are commonly accompanied by side effects. Research into the mechanisms controlling the gut inflammation offers promise for the development of novel, targeted and less toxic therapies. The major mediators of damage in IBD are white blood cells r ....Inflammatory bowel diseases (IBD) are relapsing and remitting disorders of the intestine that create substantial disability in a relatively young population of patients. Our treatments for these conditions have changed little in the last 30 years and they are commonly accompanied by side effects. Research into the mechanisms controlling the gut inflammation offers promise for the development of novel, targeted and less toxic therapies. The major mediators of damage in IBD are white blood cells recruited from the circulation to affected intestine. This recruitment is induced by the production in damaged intestine of chemokines, proteins of the immune system that attract and activate white blood cells. Chemokines act through chemokine receptors on the surface of white blood cells, and earlier research by our group has demonstrated that these chemokine receptors can be functionally modulated by neuropeptides, proteins unrelated to chemokines that normally transmit messages within the nervous system. This project aims to explore the chemokines and chemokine receptors responsible for the recruitment of white blood cells to normal and IBD-affected intestine, in order to determine therapeutic targets for novel treatments. Moreover, the role of neuropeptides in modulating the recruitment of white blood cells to the intestine will be examined in cells from the human intestine, both normal and IBD-affected, as well as in an animal model of IBD. This project will provide an understanding of the signals responsible for the attraction of damaging white blood cells to sites of inflammation in the bowel and will indicate mechanisms used by the immune system to regulate those signals. It has the potential to direct us to new therapies that use highly targeted and physiologically appropriate approaches to controlling white blood cell trafficking in health and disease.Read moreRead less
Detection Of Susceptibility Genes For Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$589,073.00
Summary
Multiple sclerosis is one of the most common chronic diseases of the nervous system. It usually starts in young adulthood and continues with episodes of severe disability from which partial recovery leads in many patients to difficulties with walking, balance, speech, bladder control and other neurologic functions. The disease inflicts a severe burden on both patients and the community. There is currently no preventive treatment and therapy is expensive (interferon at $20,000 p.a.) and of limite ....Multiple sclerosis is one of the most common chronic diseases of the nervous system. It usually starts in young adulthood and continues with episodes of severe disability from which partial recovery leads in many patients to difficulties with walking, balance, speech, bladder control and other neurologic functions. The disease inflicts a severe burden on both patients and the community. There is currently no preventive treatment and therapy is expensive (interferon at $20,000 p.a.) and of limited benefit in stopping further damage and of no benefit in reversing existing damage. New treatments will come through a full understanding of how the immune system attacks the brain to cause MS. There is a strong inherited component in MS and the discovery of the genes responsible should speed up the quest to understand the cause of the disease. The proposed studies involve international collaboration co-ordinated from Cambridge University, UK, in which the entire human genome will be screened looking for the MS genes using world s best available technology. Funding of this grant will allow Australia an equal seat at the table for this collaboration involving 17 countries. No individual country can recruit enough patients and hence this international effort is essential. It is expected that the understanding of the cause of MS will lead to new treatments that are effective and with low side effects.Read moreRead less
The Beyondblue Schools Research Initiative: A Two-year Follow-up.
Funder
National Health and Medical Research Council
Funding Amount
$827,285.00
Summary
The prevalence of Depressive Disorders among children and adolescents was estimated in the Australian National Child and Adolescent Mental Health Survey to be 3.7%. This means that at any single point of time, approximately 138,000 Australian children and adolescents are experiencing a Depressive Disorder. Furthermore, the National Survey found that less than half (46%) of those with a Depressive Disorder received any help over a 6 month period prior to the survey, with only 8% attending a menta ....The prevalence of Depressive Disorders among children and adolescents was estimated in the Australian National Child and Adolescent Mental Health Survey to be 3.7%. This means that at any single point of time, approximately 138,000 Australian children and adolescents are experiencing a Depressive Disorder. Furthermore, the National Survey found that less than half (46%) of those with a Depressive Disorder received any help over a 6 month period prior to the survey, with only 8% attending a mental health clinic, and only 4% attending a hospital-based Department of Psychiatry. These findings emphasise the importance of finding alternative approaches to help the large number of young people with depression who do not receive help from professional services. This application seeks funding to evaluate the beyondblue Schools Research Initiative. The key features of the initiative are the development of a strong partnership between the health and education sectors and a focus on both individual-level and school-level risk factors. This has enabled us to provide a much longer duration of intervention than previous studies, to test the intervention in several different Australian States, and to utilise a broadly based intervention that includes a range of approaches, each of which have the potential to help reduce adolescent depression. The significance of the project lies in its potential to identify effective interventions which can reduce rates of depression experienced by adolescents, and the quality of the ongoing research partnership we have established across the education and health sectors. We anticipate that this partnership will be utilised for ongoing research in this area.Read moreRead less
Resistant forms of childhood acute lymphoblastic leukaemia (ALL) constitute a leading cause of cancer-related deaths in children. Despite tremendous improvements in therapy, 25-30% of patients still experience a relapse and many of them occur in patients stratified as low risk. Further treatment is often toxic, frequently unsuccessful and carries the risk of significant long-term morbidity. For the design of more appropriate therapy, information on the biology of relapsed ALL is urgently require ....Resistant forms of childhood acute lymphoblastic leukaemia (ALL) constitute a leading cause of cancer-related deaths in children. Despite tremendous improvements in therapy, 25-30% of patients still experience a relapse and many of them occur in patients stratified as low risk. Further treatment is often toxic, frequently unsuccessful and carries the risk of significant long-term morbidity. For the design of more appropriate therapy, information on the biology of relapsed ALL is urgently required. The sequencing of the human genome and advanced screening technology (microarrays) allow the detailed analysis of expression patterns in large numbers of specimens. We propose to study the genetic features of this disease by investigating 28 childhood ALL patients from whom we have stored specimens received at two time points, one at diagnosis and one at relapse. The hypothesis of this study is that relapsed leukaemias display genetic features which are correlated to their resistance to therapy. The specific questions we will be asking are: (1) Which genes are expressed at high levels in leukaemia specimens at the time of relapse while not expressed (or expressed at lower levels) at the time of diagnosis and vice versa? (2) What is the function of differentially expressed genes? (3) Is the pattern of gene expression correlated with resistance to the particular drug therapy used? (4) Is the leukaemia clone at relapse related or unrelated to the clone present at diagnosis, as determined by receptor rearrangement? The expression levels of identified discriminator genes will be confirmed by real-time quantitative polymerase chain reaction (PCR). The quality of this set of specimens makes them particularly suited to achieve the stated goals, providing a unique opportunity to investigate drug resistance in childhood ALL. The data generated will provide the basis for the examination of genes suitable as new therapeutic targets.Read moreRead less
Using Evidence To Set Priorities In Health: An Analysis Of Decisions Of The Pharmaceutical Benefits Advisory Committee
Funder
National Health and Medical Research Council
Funding Amount
$174,575.00
Summary
Australia has pioneered the use of rigorous clinical and economic evidence in the evaluation of drugs prior to funding on our nationally subsidised Pharmaceutical Benefits Scheme. In the ten years since the introduction of the requirement that drugs demonstrate cost effectiveness prior to subsidy being granted there has been no formal independent evaluation of the system to assess its performance. This project will examine the recommendations of the Pharmaceutical Benefits Advisory Committee in ....Australia has pioneered the use of rigorous clinical and economic evidence in the evaluation of drugs prior to funding on our nationally subsidised Pharmaceutical Benefits Scheme. In the ten years since the introduction of the requirement that drugs demonstrate cost effectiveness prior to subsidy being granted there has been no formal independent evaluation of the system to assess its performance. This project will examine the recommendations of the Pharmaceutical Benefits Advisory Committee in the last decade and consider the factors that explain those decisions. At times it has been asserted that those decisions have been arbitrary or based on inappropriate considerations such as the financial cost to government or politics of the day rather than the value for money of the drug in question. We will examine the reasons behind the decisions against the objectives of providing access to life enhancing medicines in a cost effective manner. We will look at what are the key determinants of whether a drug is recommended for listing on the PBS or is rejected. A key focus will be on whether those determinants could be described as legitimate in terms of their consistency with the objectives of the scheme. For example whether the main cause of rejection is a lack of high quality evidence on effectiveness- cost effectiveness or simply because of factors such as the high financial cost to government. The project will create a database of all submissions to the PBAC 1992-2004 that will allow us to explore a number of questions about the effectiveness of the decision making process in using evidence on effectiveness and costs in health more broadly as well as those specific to the PBS. In highlighting some of the problems with the evidence and its interpretation the overall aim is to improve the quality of the decision making process in the future.Read moreRead less