Overweight and obesity are at epidemic proportions in Australia, reflecting the pattern in the developed and developing world. The main cause appears to be an energy mismatch, with excessive caloric consumption. One response of the body to excessive nutrient supply is energy storage in fat tissue and to aid in this the body also generates new fat tissue, termed adipogenesis (also known in cells as fat cell differentiation). In many people who gain excess body weight, fat tissue is abnormal and d ....Overweight and obesity are at epidemic proportions in Australia, reflecting the pattern in the developed and developing world. The main cause appears to be an energy mismatch, with excessive caloric consumption. One response of the body to excessive nutrient supply is energy storage in fat tissue and to aid in this the body also generates new fat tissue, termed adipogenesis (also known in cells as fat cell differentiation). In many people who gain excess body weight, fat tissue is abnormal and does not respond well to the chemical insulin, thus causing insulin resistance. This insulin resistant fat tissue is especially present in a central body (visceral) site. Insulin resistance related to this visceral fat predisposes to both diabetes and premature death from cardiovascular disease. Understanding how fat tissue develops and how it might cause insulin resistance is thus important in human health. One of the factors in fat that prevents normal development of fat tissue and which induces insulin resistance is transforming growth factor- (TGF- ). We have generated new data showing that two proteins which are increased by TGF- , termed connective tissue growth factor (CTGF) and insulin like growth factor binding protein-3, (IGFBP-3), prevent adipogenesis. We have shown this in cultured cells, and have found that CTGF and IGFBP-3 are increased in visceral fat in animal models of obesity and insulin resistance. Our preliminary work has further indicated how CTGF and IGFBP-3 might each work in the fat cell to prevent adipogenesis. This proposal will determine if TGF- works through CTGF and IGFBP-3 to block adipogenesis, and it will define how CTGF and IGFBP-3 have their inhibitory effects on fat cell differentiation. Cells in culture will be utilised and an animal model of dietary induced obesity and insulin resistance will help to define whether CTGF and IGFBP-3 prevent adipogenesis in vivo, furthering our understanding in how abnormal fat tissue may develop.Read moreRead less
Pathogenesis Of Antiretroviral Induced Sub-cutaneous Fat Wasting
Funder
National Health and Medical Research Council
Funding Amount
$331,650.00
Summary
The use of potent antiretroviral therapy has resulted in great clinical and survival benefit in patients with HIV infection and has in most cases, outweighed the risk of short term side effects. However, not that survival of patients with AIDS has considerably improved the long-term complications of chronic therapy have become a critical issue. Lipodystrophy syndrome(s) is the name given to a set of changes to blood lipids, glucose levels and body habitus and typically occurs in those successful ....The use of potent antiretroviral therapy has resulted in great clinical and survival benefit in patients with HIV infection and has in most cases, outweighed the risk of short term side effects. However, not that survival of patients with AIDS has considerably improved the long-term complications of chronic therapy have become a critical issue. Lipodystrophy syndrome(s) is the name given to a set of changes to blood lipids, glucose levels and body habitus and typically occurs in those successfully treated with anti-HIV therapy. The facial and body habitus changes are common, progressive and are frequently disfiguring. Aside from the psychological and social effects of such changes, many patiens are not able to retain their anonymity as HIV infected individuals. In addition, changes to blood lipids may lead to atherosclerosis. Already there have been several case reports of premature coronary disease in young HIV infected patients. It is increasingly difficult for patients to remain strictly adherent to chronic therapy because of all these concerns. There is an urgent need to understand the exact biological cause(s) of lipodystrophy syndrome(s) in HIV infected patients in order to help identify which of our currently available antiretroviral therapies will offer the long term clinical and survival benefit of strong viral suppression without increasing risk of vascular disease. Based on results of our previous studies on lipodystrophy syndrome, we have proposed that lipodystrophy may be the result of antiviral drugs depleting the DNA content of mitochondria within fat cells. We propose to examine sequential fat biopsy specimens from HIV infected volunteers to determine whether antiretroviral therapy has had adverse effects on mitochondrial DNA content and-or function.Read moreRead less
Making Human T- And B-lymphocytes For Immunotherapy And Antibody Production
Funder
National Health and Medical Research Council
Funding Amount
$795,880.00
Summary
Lymphocytes are white blood cells that are involved in producing antibodies, killing defective cells, or killing cells infected with viruses. In recent years, researchers have found ways to harness lymphocytes to develop medicines for treating a variety of different cancers. In this project, we will establish methods to make human lymphocytes in the laboratory from stem cells, paving the way for the broader application of this cell type to new therapies.
Lipid Metabolism In The Aromatase Knock-out Mouse (ArKO)
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermi ....Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermineralisation of the bones, intra-abdominal obesity, hypercholesterolaemia and insulin resistance. We are addressing the mechanisms of all of those phenotypes but in the present application we focus on the abnormalities in lipid metabolism. Thus we will seek to understand the increase in adiposity by examining the role of oestrogen in lipid synthesis, oxidation and breakdown in adipose tissue from intra-abdominal sites. We will also examine the role that oestrogen plays in cholesterol uptake, synthesis and catabolism by the liver as well as fatty acid synthesis and oxidation by the liver. These studies will be correlated with whole body parameters such as feeding behaviour, physical activity, energy expenditure, glucose and fat oxidation rates. We will also examine the effect of feeding a high cholesterol or a high fat diet on lipid metabolism in the oestrogen deficient animals, and we will determine the effect of oestradiol and isoflavone replacement on the phenotype. In this way we aim to reach a better understanding of the multiplicity of roles that oestrogens play in the regulation of lipid and cholesterol metabolism in both males and females. The results of such studies will be the development of better strategies to deal with pathologies resulting from disturbances in cholesterol and lipid metabolism.Read moreRead less
The Regulation Of Gene Expression During Adipogenesis
Funder
National Health and Medical Research Council
Funding Amount
$549,446.00
Summary
The body stores energy acquired from ingested food as fat droplets within storage cells termed adipocytes. The amount of fat varies between individuals and may also vary during an individual's life. The variations reflect differences in physiology, diet, and behaviour and have been the focus of intense study. Excessive accumulation of fat is a serious health problem as it is associated with conditions such as heart disease and diabetes. This grant application primarily concerns using a new line ....The body stores energy acquired from ingested food as fat droplets within storage cells termed adipocytes. The amount of fat varies between individuals and may also vary during an individual's life. The variations reflect differences in physiology, diet, and behaviour and have been the focus of intense study. Excessive accumulation of fat is a serious health problem as it is associated with conditions such as heart disease and diabetes. This grant application primarily concerns using a new line of genetically modified mice that have reduced fat. These mice lack a key gene regulatory protein that is implicated in fat accummulation and adipocyte formation. It is expected that a knowledge of the genes regulating the formation and function of fat storage cells will contribute to new strategies for controlling fat formation and will help in the prevention of diseases such as diabetes and heart disease.Read moreRead less
Regionalisation And Differentiation Of EPL-derived Neurectoderm: Directed Formation Of Dopaminergic Neurons In Vitro.
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Neurodegenerative diseases result from the loss, damage or dysfunction of neural populations. For example, dopaminergic neurons are lost progressively in Parkinson's Disease. A potential method of treatment is 'cell therapy' which envisages transplantation of cells back to the site of cell loss, and restoration of function. Application of the cell therapy approach is limited by the unavailability of cells for transplantation. Embryonic stem (ES) cells provide a potential solution to this problem ....Neurodegenerative diseases result from the loss, damage or dysfunction of neural populations. For example, dopaminergic neurons are lost progressively in Parkinson's Disease. A potential method of treatment is 'cell therapy' which envisages transplantation of cells back to the site of cell loss, and restoration of function. Application of the cell therapy approach is limited by the unavailability of cells for transplantation. Embryonic stem (ES) cells provide a potential solution to this problem because they can be grown in unlimited numbers and differentiated to any kind of cell that is found in the embryo or adult. In this application we propose to continue our work on controlling the differentiation of ES cells to neural lineages. Production of dopaminergic neurons will be a particular focus. We will establish conditions that enable the production of these cells in a manner that is therapeutically relevant and predicted to be acceptable to regulatory authorities. Cells will be tested by transplantation into adult rats to assess their therapeutic potential, in particular persistence, integration and differentiation within the brain environment. Research required to achieve the production of transplantable cells will also provide basic information about the mechanisms by which the mammalian embryo allocates cells, specifically cells of the nervous system, to specific lineages during embryogenesis. This information will be important for the production of other neural cell types, which have therapeutic potential for treatment of diseases like stroke, motor neuron disease and spinal cord injury.Read moreRead less
Analysis Of T Cell Fate Regulation By Asymmetric Cell Division
Funder
National Health and Medical Research Council
Funding Amount
$287,321.00
Summary
The aim of this research is to study how white blood cell growth is regulated by signals of the immune system. Problems in this process can have drastic effects on the well being of an individual leading to deficiencies in controlling infection and development of diseases such as cancer. Once we understand how these signals regulate white blood cell growth, we can begin to develop therapies to provide protection against these diseases.