Primary Cardiac Hypertrophy - A Functional Genetic Approach To Investigate Cellular Mechanisms Of Metabolic Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$226,692.00
Summary
Population studies have recently shown that enlargement of the heart, even when blood pressure is normal, is a risk factor which can lead to cardiovascular complications. Very little is known about the alterations in heart cell structure and function which occur in cardiac enlargement not complicated by high blood pressure. It is possible that specific metabolic abnormalities underlie this condition. The goal of this study is to use a newly developed genetically manipulated experimental animal m ....Population studies have recently shown that enlargement of the heart, even when blood pressure is normal, is a risk factor which can lead to cardiovascular complications. Very little is known about the alterations in heart cell structure and function which occur in cardiac enlargement not complicated by high blood pressure. It is possible that specific metabolic abnormalities underlie this condition. The goal of this study is to use a newly developed genetically manipulated experimental animal model to study the function of single heart cells. In this model one of the glucose transporters has been deleted. Our goal is to compare heart function in this genetic model with heart function in diabetes. Cells are isolated from hearts using enzyme treatments and investigated microscopically to determine if there are subcellular structural alterations. Functional studies are performed on individual viable cells using a combination of electrical recording techniques and fluorescence imaging methods. The experimental aim is to assess whether there is disruption of sodium, calcium or pH regulation associated with cardiac enlargement associated with metabolic abnormalities. This research will assist in identifying appropriate therapeutic strategies for intervention in the treatment or prevention of conditions associated with cardiac enlargement.Read moreRead less
ASSESSMENT OF PHOTOGRAPHY AS AN AID TO EARLY DETECTION OF MELANOMA IN OLDER MALES BY GENERAL PRACTITIONERS
Funder
National Health and Medical Research Council
Funding Amount
$36,110.00
Summary
Our previous studies have shown that older groups are more likely to present with advanced melanoma and that over half the deaths from melanoma occur in males over the age of 50. Early detection of melanoma in this group could therefore be expected to result in a major reduction in mortality from the disease. The reason for presentation with more advanced melanoma appears to be due to a high frequency of melanoma at hard to see sites such as the back and a form of melanoma (nodular melanoma) tha ....Our previous studies have shown that older groups are more likely to present with advanced melanoma and that over half the deaths from melanoma occur in males over the age of 50. Early detection of melanoma in this group could therefore be expected to result in a major reduction in mortality from the disease. The reason for presentation with more advanced melanoma appears to be due to a high frequency of melanoma at hard to see sites such as the back and a form of melanoma (nodular melanoma) that is hard to recognise in its early stages. Older people also are less able to recognise changes of melanoma. Our previous studies also showed that both doctors and lay people have poor ability to recognise changes in skin lesions over time but can do so if a photographic record is available. We wish therefore to evaluate in pilot studies whether a screening service based on photographic records taken at age 50 will assist in the early detection of melanoma in this age group. A pilot study is necessary to evaluate the feasibility of recruitment procedures, acceptability to doctors and cost-effectiveness. We have made substantial progress and are requesting another years funding to complete the study and its analysis. If the project is successful it is intended to conduct a larger randomised trial in the Hunter Region to evaluate this approach to screening. Thickness of the primary melanoma and survival from melanoma will be used as the endpoints.Read moreRead less
An Integrated Psychoacoustic And High-field FMRI Study Of Auditory Temporal Processsing Dysfunction In Schiophrenia.
Funder
National Health and Medical Research Council
Funding Amount
$306,000.00
Summary
This research seeks to improve our understanding of the causes of brain dysfunction in schizophrenia. This chronic and debilitating psychiatric disorder is usually accompanied by dramatic symptoms such as hallucinations, delusions, paranoia and disordered patterns of thinking. Based on our interpretation of evidence from a number of fields of schizophrenia research we suspect that the brain dysfunction in schizophrenia may not in the brain areas responsible for those dramatic symptoms but occurs ....This research seeks to improve our understanding of the causes of brain dysfunction in schizophrenia. This chronic and debilitating psychiatric disorder is usually accompanied by dramatic symptoms such as hallucinations, delusions, paranoia and disordered patterns of thinking. Based on our interpretation of evidence from a number of fields of schizophrenia research we suspect that the brain dysfunction in schizophrenia may not in the brain areas responsible for those dramatic symptoms but occurs initially in the very basic sensory regions of the brain. These regions can be thought of as providing the building blocks of our perceptions, that ultimately allow us to see, hear, smell and feel. Our previous research shows that people with schizophrenia have a very specific problem in the way that they perceive sounds. Using measures of brain activity, people with schizophrenia show consistent evidence that their brains do not process some of the timing information contained in sound. This is not the same as saying that people with schizophrenia are deaf, the deficits we see are much more subtle. It's a bit like the chaos theory analogy of a butterfly fluttering in Brazil and causing a typhoon in China. We think that very small alterations in brain activity in the initial stages of sensory processing can cascade through successively more complex stages of the brain, eventually creating the psychotic storm that becomes evident as the primary symptoms of schizophrenia. The brain regions we are interested in are located down at the base of the brain, in the brainstem, and it is only recently that the technology and methods of analysis we need to look at this activity have been developed. In this research we will be using functional magnetic resonance imaging and sophisticated hearing tests to examine whether these brain regions show the alterations we expect. If so, this will mean that the brain dysfunction in schizophrenia is quite different to what is currently believed.Read moreRead less
Explaining The Dark Matter Of Genome-wide Association Studies For Complex Disease
Funder
National Health and Medical Research Council
Funding Amount
$453,098.00
Summary
Common diseases, such as psychiatric disorders and cardiovascular disease, are caused by the interplay of genetic and envirionmental factors. In the last 4 years, very large studies have been conducted to associate genetic factors with risk of disease, but these studies have not accounted for known familial risk. We aim to use data on very distant relatives to explain why. Understanding the genetic basis of common disease is crucial to guide future experiments and for developing new treatments.
The Role Of Nutrition In Disease-linked Epigenetic Inheritance
Funder
National Health and Medical Research Council
Funding Amount
$485,412.00
Summary
This project aims to investigate one mechanism behind fetal programming, in which a suboptimal in utero environment can affect health of offspring in later life. We and others have recently shown that fetal programming can be caused by changes in the way genes behave, and we will examine how many genes are affected by these changes. We will ask whether the changes can increase in frequency with long-term exposure to nutritional stress, and become entrenched within the population.
Spatio-temporal Analysis Of Rat Intestinal Motility In Physiological And Disease Models
Funder
National Health and Medical Research Council
Funding Amount
$358,750.00
Summary
This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping ....This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping behaviour to prevent over-filling or to eject toxic or irritating substances (eg: some laxatives activate this mechanisms). This is often called peristalsis. A third mechanism consists of activity of nerve cells in the gut, that slowly propagates along the intestine and causes the muscle to contract, sweeping along any remnants. The movements generated by these three mechanisms occur in segments of intestine isolated from rats. The major difficulty up until now has been to relate the actual movements in living animals to these fundamental mechanisms. It is now possible to bridge this gap because we have developed methods to record, display and measure graphically the actual movements. Movements are transformed into spatio-temporal maps which show all of the contractions over a period of time. Coordinated activity is visible in these maps as recognisable patterns or visual objects. Measurements can be readily made with conventional statistics. The literature in gastroenterology is full of descriptions of motility based on indirect methods of recordings. In this project we will be able to correlate the previous indirect methods with the new graphic methods and thus establish a clearer, simpler and more accurate classification of normal patterns of intestinal motility. We will then use this to establish what goes wrong in a number of experimental diseases known to affect adversely the movements of the intestine.Read moreRead less
Function Of The Lysophospholipid Receptor Family In Neuronal Stem Cells And Their Progenitors.
Funder
National Health and Medical Research Council
Funding Amount
$380,723.00
Summary
Stem cells have the potential to give rise to a vast array of differentiated cells. Neuronal stem cells (NSC) can differentiate into progenitor cells which can themselves differentiate into cells of the nervous system: neurons and macroglial cells (astrocytes, oligodendrocytes, Schwann cells). This in turn can assist in the treatment of degenerative diseases such as multiple sclerosis, Parkinson's disease, motoneuron desease etc. Our project aims to study the effects on NSC and their progenitor ....Stem cells have the potential to give rise to a vast array of differentiated cells. Neuronal stem cells (NSC) can differentiate into progenitor cells which can themselves differentiate into cells of the nervous system: neurons and macroglial cells (astrocytes, oligodendrocytes, Schwann cells). This in turn can assist in the treatment of degenerative diseases such as multiple sclerosis, Parkinson's disease, motoneuron desease etc. Our project aims to study the effects on NSC and their progenitor cells of the lysophospholipids lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), bioactive molecules known to play an essential role in the nervous system during development and inflammation. Our project aims to understand the mechanisms of action of these molecules in NSC maintenance, proliferation, differentiation and migration. By understanding how these molecules are able to regulate NSC biology will provide new avenues in the development of tools necessary for stem cell therapy.Read moreRead less
Regulation Of The Drosophila C-Myc Homologue In Stem Cell Growth And Division.
Funder
National Health and Medical Research Council
Funding Amount
$613,397.00
Summary
The mechanisms controlling stem cell growth and division require elucidation if we are to use stem cells in regenerative medicine and find cancer treatments. Due to experimental limitations such mechanisms are largely unknown in humans. We aim to use the vinegar fly as a model system to understand the importance of microenvironment to cancer gene control in stem cells. We will identify the secreted signals, from the neighbouring cells, required to control cancer initiation in stem cells.