Macrophage Migration Inhibitory Factor (MIF) And P53 In Rheumatoid Arthritis .
Funder
National Health and Medical Research Council
Funding Amount
$333,055.00
Summary
Rheumatoid arthritis (RA) is an inflammatory disease affecting approximately 1% of the population. It is characterised by severe inflammation and destruction of joints resulting in significant health problems. The lining tissue of joints is known to be infiltrated by inflammatory cells. In addition to this infiltration of inflammatory cells, there is overgrowth of the normal lining cells of joints. These overgrowing cells contribute significantly to joint damage by invading cartilage and bone an ....Rheumatoid arthritis (RA) is an inflammatory disease affecting approximately 1% of the population. It is characterised by severe inflammation and destruction of joints resulting in significant health problems. The lining tissue of joints is known to be infiltrated by inflammatory cells. In addition to this infiltration of inflammatory cells, there is overgrowth of the normal lining cells of joints. These overgrowing cells contribute significantly to joint damage by invading cartilage and bone and allowing inflammatory cells to reach these areas. The abnormal growth of these cells has been related to the malfunction of certain genes that usually restrain abnormal growth. These genes called tumour suppressor genes are known to be damaged in joint lining cells derived from RA. The best known of these abnormal tumour suppressor genes is called p 53. The product of the p53 gene, the p 53 protein, is particularly important in slowing down the growth of cells. The applicant has recently shown that an inflammatory product called MIF is released in large quantities by joint lining cells in RA. Previous studies by the applicant have shown that blocking MIF using an antibody almost completely prevents arthritis development in a rat model. These studies indicate that MIF is likely to be an important contributor to disease in RA. Recent preliminary studies in the applicant s laboratory have shown that MIF can decrease p53 levels in joint lining cells from RA patients and also that MIF can increase the growth rate of these cells. These preliminary data indicate that MIF may contribute significantly to disease in RA by overriding control of normal cell growth by p53. Confirmation and full exploration of the regulation of p53 expression and function by MIF may highlight a novel way to treat the excessive growth and invasion by joint lining cells which characterises RA.Read moreRead less
Anti-apoptotic, Anti-fibrotic, And Positive Inotropic Effects Of Ghrelin And GHRP On Rat And Mouse Cardiac Myocytes
Funder
National Health and Medical Research Council
Funding Amount
$442,530.00
Summary
Growth hormone (GH) is a protein hormone secreted from an endocrine organ, the pituitary gland, below the brain. Synthetic GH-releasing peptides (GHRPs) and endogenous GHRP (ghrelin) possess many other physiological functions in addition to the release of GH. GHRPs have been shown to affect cardiac function in animals and humans through their specific receptors. We recently demonstrated at single cell level that GHRPs increased contraction of cardiac muscle cells and protected them from the prog ....Growth hormone (GH) is a protein hormone secreted from an endocrine organ, the pituitary gland, below the brain. Synthetic GH-releasing peptides (GHRPs) and endogenous GHRP (ghrelin) possess many other physiological functions in addition to the release of GH. GHRPs have been shown to affect cardiac function in animals and humans through their specific receptors. We recently demonstrated at single cell level that GHRPs increased contraction of cardiac muscle cells and protected them from the programmed cell death which occurs in heart failure and myocardial infarction. We also demonstrated that GHRPs protected the heart in chronic heart failure and alleviated functional loss of the heart in experimental heart failure models. Preliminary results now indicate that GHRPs prevent cardiac fibrosis, which accounts for cardiac dysfunction after heart failure and infarction. It is proposed in this project to clarify the mechanism underlying the action of GHRPs in (1) cardiac functional enhancing; (2) anti-cell death; (3) anti-fibrosis effects, in primary cultured rat myocytes in vitro and in cardiac diseased mouse models in vivo. By completing this project, we will be able to (1) better understand the physiological role of ghrelin in the regulation of cardiac function; and (2) clarify the potential for therapeutic use of GHRPs in the treatment of chronic heart failure, a disease affecting 1-2% of the population of Australia, with 5 year mortality rates about 65%.Read moreRead less
Regulation Of Brain Development By Members Of The Fibroblast Growth Factor Family
Funder
National Health and Medical Research Council
Funding Amount
$65,685.00
Summary
The brain is the most complex organ in the body. It is made up of many different types of cells broadly classified into two classes called neurons and glia. The growth of the brain from a small population of immature neuroepithelial cells to many different types of neurons and glia is controlled by small potent proteins called growth factors. We understand that many different families of growth factors are involved in the development of the brain but not how they do what they do. We are studying ....The brain is the most complex organ in the body. It is made up of many different types of cells broadly classified into two classes called neurons and glia. The growth of the brain from a small population of immature neuroepithelial cells to many different types of neurons and glia is controlled by small potent proteins called growth factors. We understand that many different families of growth factors are involved in the development of the brain but not how they do what they do. We are studying the members of one particular family known as the Fibroblast Growth Factor family or FGFs. We want to find out how they instruct young brain cells to grow and divide and turn into mature neurons.Read moreRead less
The Regulation Of Pleiotropic Responses By Bidentate Motifs Embedded In The Fibroblast Growth Factor Receptors
Funder
National Health and Medical Research Council
Funding Amount
$489,336.00
Summary
Cells in our bodies are able to accomplish an impressive array of functions. Diffusible factors (called growth factors) are important in regulating diverse cellular functions. We have identified a new molecular switch inside cells that acts as a master controller of cellular functions. This molecular switch relays information to instruct specific cellular functions. We have shown that these molecular switches are short-circuited in breast cancer promoting cell growth and survival.
Therapeutic Targeting Of A New Growth Factor In Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$317,775.00
Summary
Malignant mesothelioma is an aggressive and incurable cancer. This study will build on our recent data showing a protein termed FGF-9, not previously linked with mesothelioma, could significantly stimulate mesothelioma growth. This project will examine the biologic activities of FGF-9 and its receptors in mesothelioma, and the therapeutic benefits of antagonizing FGF-9 in mesothelioma in vivo.
Aberrant Signalling Through Gp130 In The Pathogenesis Of Fibrotic Lung Diseases
Funder
National Health and Medical Research Council
Funding Amount
$456,500.00
Summary
Pulmonary fibrosis is a chronic diffuse interstitial lung disease of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation. Data generated over the past deca ....Pulmonary fibrosis is a chronic diffuse interstitial lung disease of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation. Data generated over the past decade also have established the concept that the molecular processes underlying the fibrogenesis component may represent a new opportunity for therapeutic intervention. Attempts to treat fibrosis have for the most part consisted of anti- inflammatory drugs, almost exclusively steroids. The effectiveness of steroids is variable and can be associated with significant side effects. This project will examine the effects of a family of molecules called cytokines that signal through gp130 as critical determinants of disease susceptibility and progression. gp 130 is a shared component in the receptor complexes for IL-6 family cytokines (IL-6, IL-11, LIF, OSM) which are important regulators of both the phenotype and proliferation of fibroblasts in health and in response to injury. Our data raises the possibility of developing pharmacological manipulators of gp130 signalling pathways that would suppress fibrosis but leave normal cellular defense mechanisms necessary for host defense in the lung intact.Read moreRead less