Identifying A Novel Role For Pigment Epithelium-derived Factor In Obesity-related Metabolic Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$361,637.00
Summary
Obesity is an important factor contributing to insulin resistance and type 2 diabetes; however, the factors linking these disorders are not well defined. A protein called PEDF is elevated in obesity and type 2 diabetes. This project will examine how PEDF causes insulin resistance and whether blocking PEDF's actions prevents insulin resistance. Successful completion of this project may lead to therapeutics that reduce the risk of developing type 2 diabetes.
NOVEL REGULATORS OF CONNECTIVE TISSUE GROWTH FACTOR EXPRESSION AND BIOACTIVITY IN DIABETIC COMPLICATIONS
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Diabetes mellitus is common in our community. It causes much premature death and loss of quality of life. Recent data from Australian studies show that ~7% of adults over 25 years, and ~20% of people aged over 65 have diabetes, and diabetes in both children and adults is increasing in Australia. A critical problem caused by diabetes, irrespective of its cause, is that blood glucose levels are higher than normal. High blood glucose contributes to much of the damage to body tissues and to the earl ....Diabetes mellitus is common in our community. It causes much premature death and loss of quality of life. Recent data from Australian studies show that ~7% of adults over 25 years, and ~20% of people aged over 65 have diabetes, and diabetes in both children and adults is increasing in Australia. A critical problem caused by diabetes, irrespective of its cause, is that blood glucose levels are higher than normal. High blood glucose contributes to much of the damage to body tissues and to the early death that can occur in diabetes. Unfortunately, given our current treatment methods, in only a small number of patients can glucose levels in the body be consistently controlled into the normal range. How does high blood glucose cause damage to the body and its different tissues? This is a complex process. One way that damage occurs is through an increase in some of the growth factors in the body. In diabetes, high blood glucose can increase the production of some growth factors in an uncontrolled way. In turn, these growth factors then cause tissue damage. One of the growth factors that can be increased by the high glucose in diabetes is called connective tissue growth factor, or CTGF. CTGF can cause scars to form in tissues, and it is increased in diabetes in humans. Through NHMRC sponsored post-doctoral research over the past four years, Dr Twigg has published findings showing pathways by which diabetes causes increases in CTGF, and ways in which CTGF then causes tissue scarring. The current grant proposal presents new data showing further novel pathways by which CTGF is activated by diabetes and ways in which CTGF causes scarring. The pathways involved will be studied in detail in the project. In addition, methods to block CTGF and its harmful effects in diabetes will be developed in this work. By controlling CTGF, it is envisaged that damage to tissues will be reduced, leading to improved quality and quantity of life for people who have diabetes.Read moreRead less
Metabolic Wiring In Adipocytes - Unique Role In Maintaining Long-term Health
Funder
National Health and Medical Research Council
Funding Amount
$1,077,886.00
Summary
Fat cell metabolism is wired to optimize the cell’s ability to make and store lipid while programming the cell to fulfil its function in whole body metabolism. We will: 1) map fat cell metabolism under optimal and insulin resistant conditions; 2) explore the role of 3 nodes in his metabolic circuit predicted as control points; 3) use a novel genetically engineered mouse model to explore the functional significance of fat cell metabolism in whole body insulin sensitivity.
Most common diseases of ageing like diabetes and cancer have proven intractable because much of our knowledge is limited to individual molecules. This proposal takes a global approach to complex diseases, utilising quantitative high-resolution methods and computational modelling. This research will lead to a completely new way of thinking about complex diseases providing a range of completely novel treatment options.
Identifying The Critical Components Of Growth Factor-mediated Survival Pathways
Funder
National Health and Medical Research Council
Funding Amount
$589,338.00
Summary
The regulation of cell lifespan (cell survival) is controlled by growth factors and lies at the heart of all biological processes. However, little is known of the molecular switches inside cells that either turn survival on or off. We propose to identify and characterize the molecular switches inside cells that control the balance between cell survival and death. Targeting specific components of these switches may provide new approaches for the treatment of cancer and infectious diseases.
Transcription-based Identification Of Insulin Resistance Subtypes
Funder
National Health and Medical Research Council
Funding Amount
$341,883.00
Summary
A key feature of type 2 diabetes is the failure of metabolic tissues such as muscle and fat to respond to normal levels of insulin. This 'insulin resistance' is caused by a number of mechanisms. We will use cutting-edge technology to identify small sets of genes that define each variety of insulin resistance. These gene sets will be used to diagnose sub-types of insulin resistance and will facilitate the development of personalised therapies to effectively treat individuals with type 2 diabetes.
Ciliary Neurotrophic Factor: A Novel Theraputic Agent For The Prevention Of Muscle Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$602,673.00
Summary
In 1995 leptin was discovered and scientists world-wide hoped that this was the great panacea in the treatment of obesity related disorders. Alas, from 1995-1997 the identification of a novel cytokine inducible compound termed suppressor of cytokine signaling (SOCS) that negatively regulated leptin signalling and lead to leptin resistance, quashing hopes for a viable anti-obesogenic drug. Recently, however, work from our group has demonstrated that the neuropoietic cytokine, ciliary neurotrophic ....In 1995 leptin was discovered and scientists world-wide hoped that this was the great panacea in the treatment of obesity related disorders. Alas, from 1995-1997 the identification of a novel cytokine inducible compound termed suppressor of cytokine signaling (SOCS) that negatively regulated leptin signalling and lead to leptin resistance, quashing hopes for a viable anti-obesogenic drug. Recently, however, work from our group has demonstrated that the neuropoietic cytokine, ciliary neurotrophic factor (CNTF), can act in an anti-obesogenic fashion in a manner similar to leptin. However, unlike leptin, when we place rodents on a high fat diet, the effects of CNTF persist and override induction SOCS proteins. This project will examine the biochemical pathways that allow the actions of CNTF to persist in the presence of diet-induced obesity. This is of major significance because in completing this work, the potential for the development of peripheral tissue drug targets for the treatment of obesity related diseases are both tangible and realistic.Read moreRead less
I am a cell biologist-whole body physiologist determining the cellular and molecular mechanisms that lead to insulin resistance in insulin sensitive tissues such as skeletal muscle, liver and adipose tissue. My work primarily focuses on the role of inflam