A Novel Cardiac Inotropic Mechanism That Provides Functional Benefit
Funder
National Health and Medical Research Council
Funding Amount
$413,936.00
Summary
Patients with heart failure are often treated with an inotropic agent to increase the force of the heart's contraction and thus improve quality of life for these patients. Most inotropic agents have deleterious effects that limit their usefullness. Mice that have increased alpha1-A receptor expression in their hearts have heightened contactility that is not associated with hypertrophy or arrhythmias. We will use microarray, and si-RNA delivery and signalling studies to identify the mechanism.
The Role Of Liver Fructose-1,6-phosphatase (FBPase) In Body Weight Regulation
Funder
National Health and Medical Research Council
Funding Amount
$494,718.00
Summary
We have shown that fructose-1,6-bisphosphatase (FBPase), an enzyme important in producing sugar from the liver and one that is connected to Type 2 diabetes, does not cause an increase in sugar production when there is more of the enzyme in mouse livers. It does, however, lower both body weight and the amount of food the mice consume. We therefore hypothesise that liver FBPase is important in controlling body weight in humans and our project aims to find out exactly how and why this happens.
Type 2 diabetes is caused by multiple genetic defects, resulting in high blood sugar levels. These high sugar levels are primarily due to a decrease in the concentration of insulin, a hormone produced by the pancreas. A number of recent studies have aimed to identify which genes are regulated under conditions that mimic diabetes. One gene shown to have altered expression levels under these conditions is an enzyme called fructose-1,6-bisphosphatase (or FBPase). This enzyme is involved in the meta ....Type 2 diabetes is caused by multiple genetic defects, resulting in high blood sugar levels. These high sugar levels are primarily due to a decrease in the concentration of insulin, a hormone produced by the pancreas. A number of recent studies have aimed to identify which genes are regulated under conditions that mimic diabetes. One gene shown to have altered expression levels under these conditions is an enzyme called fructose-1,6-bisphosphatase (or FBPase). This enzyme is involved in the metabolism of sugar and is usually expressed at undetectable levels in the pancreas, but when blood sugar levels are high, the amount of FBPase in the pancreas increases considerably. We hypothesise that this increase in FBPase may contribute to the decrease in insulin secretion by the pancreas, seen in the diabetic state. The aim of this proposal therefore is to study mice that we have modified to express increased FBPase specifically in the pancreas, in order to determine whether this will lead to a decrease in insulin release and to diabetes. If this is the case, then FBPase could be targeted for the development of drugs that would improve the control of blood sugar levels in diabetes.Read moreRead less
Effect Of Aging And Mitochondrial Dysfunction On The Optic Nerve Response To Pressure-induced Oxidative Stress
Funder
National Health and Medical Research Council
Funding Amount
$415,554.00
Summary
The risk of glaucoma, a potentially blinding disease of the optic nerve, increases exponentially with age, but the cellular mechanisms responsible are not known. We hypothesise that age-related changes in mitochondria, the energy producing part of the cell, render nerve cells prone to damage. This project will determine whether aging and mitochondrial impairment increase nerve damage and whether dietary moodifications that preserve mitochondria during aging, protect the optic nerve from damage
Altered Gp130-mediated Signalling In The Regulation Of Pulmonary Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$373,956.00
Summary
Pulmonary fibrosis is a chronic diffuse interstitial lung disease often 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 using anti- inflammatory dru ....Pulmonary fibrosis is a chronic diffuse interstitial lung disease often 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 using anti- inflammatory drugs, almost exclusively steroids. The effectiveness of steroids is variable although generally poor and can be associated with significant side effects suggesting that other approaches need to be considered. Data generated over the past decade also have established the concept that the molecular processes underlying the development of fibrosis may represent a new opportunity for therapeutic intervention. This project will build on previous studies examining 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 and can signal down two major pathways. We have shown that the development of lung fibrosis depends on which specific signalling pathway is used. This study will determine how fibrosis is controlled by these pathways. 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
We will use genetically engineered mice to study brain circuitry in an effort to understand the anatomical basis of Huntington's disease and a number of other more common degenerative brain diseases similar to Parkinson's disease. We will look at the brain in detail to decipher how the injured brain repais itself by making new connections and by producing new cells. We will also study supporting cells in the brain to determine if they play a beneficial role in this injury repair process.
Functional Analysis Of The Notch Signalling Pathway In The Differentiation And Maintenance Of Pituitary Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$421,320.00
Summary
Many of the processes that are essential for normal bodily function such as growth, the ability to cope with stress, sexual organ development, metabolism and milk production, are controlled by the pituitary gland. This organ is located at the base of the brain and regulates these bodily functions through the release of six different hormones. Formation of the pituitary gland occurs during development of the foetus. This process requires a specific set of genes that shape the pituitary and allow ....Many of the processes that are essential for normal bodily function such as growth, the ability to cope with stress, sexual organ development, metabolism and milk production, are controlled by the pituitary gland. This organ is located at the base of the brain and regulates these bodily functions through the release of six different hormones. Formation of the pituitary gland occurs during development of the foetus. This process requires a specific set of genes that shape the pituitary and allow the hormone secreting cells to arise. Changes in these pituitary formation genes results in underdevelopment of the pituitary in newborn babies. In severe cases, where the pituitary has failed to form completely (panhypopituitarism), these babies are extremely ill and in some instances do not survive. We are studying the genes that belong to the Notch signalling pathway. These genes are important regulators of cell differentiation during the development of the brain, skin, bone and many other tissues. However, the role of the Notch signalling genes in pituitary development is not known. We have shown for the first time that these genes are active during pituitary development. To test the function of these genes in the pituitary, we will generate mouse models that either lack or inappropriately activate these genes. Our results will provide insight into the role of Notch Signalling genes in pituitary development in mice and humans. In this project, we also hope to identify cells in the pituitary that are able to give rise to multiple hormone secreting cell types. These stem cells are of significant clinical importance as they provide an avenue for the development of novel therapies for pituitary disorders in humans, based on the replacement of defective pituitary tissue with functional stem cell derived tissue.Read moreRead less
Many people with organ failure need a transplant to survive. Unfortunately most patients who would benefit from a transplant are unable to receive one because of the shortage of living or deceased donors. A possible solution to this shortage is to use animal organs. Pigs are the most suitable animal donor. This project aims to produce and test genetically modified pigs which can provide organs that will be resistant to rejection when transplanted into human recipients.