The Role Of Cholesterol In Patched/hedgehog Signalling During Mammalian Development.
Funder
National Health and Medical Research Council
Funding Amount
$198,660.00
Summary
Fluctuations in levels of cholesterol during development of the mammalian embryo have been shown to have catastrophic affects leading to gross deformities particularly in terms of brain and facial development. The requirement of the developing embryo for cholesterol has been linked to the patched-hedgehog signalling pathway which we have previously shown to be central to mammalian development as well as tumour formation. In particular, the patched protein which is responsible for regulating sign ....Fluctuations in levels of cholesterol during development of the mammalian embryo have been shown to have catastrophic affects leading to gross deformities particularly in terms of brain and facial development. The requirement of the developing embryo for cholesterol has been linked to the patched-hedgehog signalling pathway which we have previously shown to be central to mammalian development as well as tumour formation. In particular, the patched protein which is responsible for regulating signalling through this complex cascade of protein interactions has a domain similar to that which in other proteins has been shown to detect and respond to intracellular levels of cholesterol. The patched protein binds to hedgehog at the surface of the cell and mediates the transduction of the the hedgehog signal into the cell. By analogy to the role of sterol sensing domains in other proteins, we hypothesise that this domain in patched detects fluctuations in intracellular cholesterol levels which in turn alter trafficking of patched to the cell surface where it can participate in the hedgehog receptor complex. This hypothesis is supported by our preliminary data which suggests that patched is normally localised both at the cell surface and intracellularly. We are proposing a series of experiments to test our hypothesis, most of which deal with determing the localisation of patched in a cell culure system exposed to agents aimed at varying the intracellular levels of cholesterol. Subcellular localisation of patched will be analysed by immunofluorescence, electron microscopy and immunoblotting analysis. We will also test the ability of patched to aggregate at the cell surface with other molecules important in receiving and sending the hedgehog signal. The experiments in this proposal are likely to give the first clues as to the function of the sterol sensing domain in patched and its role in mediating the vital link between cholesterol and embryonic development.Read moreRead less
Characterising The Role Of MID1 In X-linked Opitz Syndrome: Implications For CATCH22 And Related Disorders
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Opitz syndrome is a debilitating genetic disorder which affects the normal development of many organs and tissues of the human embryo. Patients with Opitz syndrome commonly present with facial deformities (such as cleft lip and palate) as well as both genital and heart defects. Males are usually more severely affected than females although the severity of the disease can vary even amongst males of the same family. Patients can die suddenly in infancy or suffer further developmental impairment du ....Opitz syndrome is a debilitating genetic disorder which affects the normal development of many organs and tissues of the human embryo. Patients with Opitz syndrome commonly present with facial deformities (such as cleft lip and palate) as well as both genital and heart defects. Males are usually more severely affected than females although the severity of the disease can vary even amongst males of the same family. Patients can die suddenly in infancy or suffer further developmental impairment due to respiratory complications and swallowing difficulties that result from the significant facial deformities. A brighter outlook for patients is expected if early and often repeated surgical repair is undertaken to correct not only the facial deformities but also any heart and genital abnormalities. Our research laboratory has recently identified the gene that, when mutated, causes one form of Opitz syndrome. Defects in this gene account for around half the cases with the disorder. Evidence suggests that there may be a number of other genes involved in causing the remaining cases of the disease. The proposed research is aimed at investigating the molecular and developmental mechanisms that go awry as a result of the gene mutation. It is anticipated that these studies will provide valuable scientific knowledge about why some patients are more severely affected than others as well as offering clues to the identity of the genes that cause the remaining cases of Opitz syndrome. The results also have potentially important implications for the understanding of other diseases that show similar deformities. The knowledge gained from this research is expected to provide a valuable aid for effective genetic counselling (as well as the option of prenatal diagnosis) for families at risk of further affected pregnancies. This will also ultimately lead to more effective disease management and correction in the affected child.Read moreRead less
The Nutritional Geometry Of Ageing In A Rodent Model
Funder
National Health and Medical Research Council
Funding Amount
$979,269.00
Summary
A central belief in ageing research is that eating fewer calories prolongs life, and that the source of calories (carbohydrate, fat or protein) is irrelevant. However, a critical assessment indicates that this conclusion is premature. We will use recent techniques in nutrition to define for the first time in mammals the relationship between diet and ageing in a normal and a prematurely ageing strain of mice. The project will provide a novel nutritional approach for promoting healthy ageing.
Improving Breathing Support For Newborn Infants In Non-Tertiary Centres: The HUNTER Trial
Funder
National Health and Medical Research Council
Funding Amount
$1,203,844.00
Summary
Every year in Australia, thousands of newborn babies have breathing difficulties. Our trial will study a new, simple method of providing breathing support to newborn babies in special care nurseries, called high-flow (HF). HF is cheaper, easier to use, and more comfortable for babies than the current standard treatment, called CPAP. If HF is as good as CPAP at supporting babies' breathing, it will change practice in Australia and around the world.
My projects are associated with three research themes: psychological stress, obesity and hypertension. While these projects may appear diverse they are linked, both in terms of the significant co morbidity that they share, and that the underlying pathologies are initiated and sustained, at least in part, by disturbances in sympathetic nervous regulation. My research program will focus on these conditions and, in their content, will aim to develop and implement improved treatment srategies in the ....My projects are associated with three research themes: psychological stress, obesity and hypertension. While these projects may appear diverse they are linked, both in terms of the significant co morbidity that they share, and that the underlying pathologies are initiated and sustained, at least in part, by disturbances in sympathetic nervous regulation. My research program will focus on these conditions and, in their content, will aim to develop and implement improved treatment srategies in these areas of major clinical need.Read moreRead less
Old age is the main risk factor for atherosclerosis, which is the main cause of mortality and morbidity in the World. We found age-related changes in the microcirculation of the liver called pseudocapillarization that provide a mechanism linking old age with atherosclerosis. Pores in the endothelium called fenestrations disappear, impairing the ability of the liver to breakdown fats. New therapies to treat and prevent age-related pseudocapillarization are being developed.
Investigating Role Of Insulin Resistance And Sympathetic Nervous System In Metabolic Features Of PCOS
Funder
National Health and Medical Research Council
Funding Amount
$150,468.00
Summary
PCOS affects 9-18% of Australian reproductive aged women. Whilst reproductive features are prominent, PCOS has major psychological and metabolic consequences. Emerging data implicate the involvement of the sympathetic nervous system in PCOS. The aim of this PhD is to investigate the role of the sympathetic nervous system in insulin resistance and other metabolic features of PCOS and determine whether modification of this system's activity will favorably influence the metabolic consequences assoc ....PCOS affects 9-18% of Australian reproductive aged women. Whilst reproductive features are prominent, PCOS has major psychological and metabolic consequences. Emerging data implicate the involvement of the sympathetic nervous system in PCOS. The aim of this PhD is to investigate the role of the sympathetic nervous system in insulin resistance and other metabolic features of PCOS and determine whether modification of this system's activity will favorably influence the metabolic consequences associated with PCOS.Read moreRead less
Genetic And Molecular Dissection Of Laterality In The Developing Heart
Funder
National Health and Medical Research Council
Funding Amount
$379,370.00
Summary
Vertebrate animals display an external bilateral symmetry. However, most internal organs are located asymmetrically and show profound left-right structural asymmetries during development. For each species, these laterality characteristics are constant. Inherited laterality disorders occur in humans and, although rare, are associated with high mortality rates due to discordant cardiovascular development. Moreover, subtle anomalies of laterality may underlie a host of congenital heart abnormalitie ....Vertebrate animals display an external bilateral symmetry. However, most internal organs are located asymmetrically and show profound left-right structural asymmetries during development. For each species, these laterality characteristics are constant. Inherited laterality disorders occur in humans and, although rare, are associated with high mortality rates due to discordant cardiovascular development. Moreover, subtle anomalies of laterality may underlie a host of congenital heart abnormalities. In early embryogenesis, the newly-formed heart tube loops to the right, an event which establishes the correct alignment of the future cardiac chambers. The direction of heart looping is determined by genetic pathways that establish laterality in the early embryo. A component of this pathway is a TGFbeta-family signalling molecule, nodal, which is activated on the left side of the forming heart and other organs. Nodal then activates the transcription factor gene Pitx2. The aim of this project is to examine the consequences of genetic inactivation of the mouse nodal and Pitx2 genes in the heart, and to discover cardiac genes downstream of these genes. We will specifically test the hypothesis that laterality contributes to heart chamber formation in addition to setting the direction of looping. Ablation of these genes in the whole embryo leads to complex defects that preclude analysis of their functions in the heart. To achieve heart-specific deletion, we will use a conditional gene ablation technology that exploits the bacteriophage recombinase, Cre. Genes downstream of Pitx2 and Nodal will be discovered using microarray technology, which allows us to screen exhaustively for changes in gene expression between different tissues. This project will help us solve the complex genetic basis of congenital cardiac abnormalities in humans, and will contribute to our understanding of how heart chambers form, potentially useful in stem cell-based therapies for the failing heart.Read moreRead less