Obesity, Insulin Resistance And Hepatocarcinogenesis: Metabolic Mediators And Molecular Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$199,485.00
Summary
Liver cancer (or hepatocellular carcinoma, HCC) is the 3rd most common cause of cancer death, with the incidence in Australia increasing. Recently, it has been shown that obesity, diabetes and fatty liver disease can lead to HCC; this project will explore how metabolic diseases promote HCC. The role of insulin and fatty acids in promoting DNA damage and cell growth will be examined. Understanding how metabolic disease increases HCC risk will improve prevention strategies and possible treatments.
Cellular And Molecular Mechanisms Of The Profibrogenic Effect Of Leptin In The Liver.
Funder
National Health and Medical Research Council
Funding Amount
$166,500.00
Summary
Cirrhosis of the liver in the 7th leading cause of death. Regardless of the underlying cause of liver injury (virus, alcohol, or in affluent countries non-alcoholic steatohepatitis -NASH), the liver repairs damage by forming scar tissue in a pocess similar to wound healing. All chronic liver diseases are associated with repeated rounds of wound-healing leading inevitably to progressive fibrosis and cirrhosis of the liver. Obesity, in addition to being linked to type II diabetes and cardiovascula ....Cirrhosis of the liver in the 7th leading cause of death. Regardless of the underlying cause of liver injury (virus, alcohol, or in affluent countries non-alcoholic steatohepatitis -NASH), the liver repairs damage by forming scar tissue in a pocess similar to wound healing. All chronic liver diseases are associated with repeated rounds of wound-healing leading inevitably to progressive fibrosis and cirrhosis of the liver. Obesity, in addition to being linked to type II diabetes and cardiovascular diseases, is an independent risk factor for liver injury. It is the clinical setting for NASH, the most common liver disorder in western countries. Also the severity of hepatic fibrosis and the risk of progression to fibrosis in most forms of liver diseases (regardless of their cause) are dramatically increased in overweight (>60%) and obese (20% of adult Australian) patients. Leptin is an hormone that primarily controls food intake and energy balance in the body. In addition, leptin has many other functions. It is a modulator of the immune and inflammatory system, it is involved in skin wound healing and increases sclerosis in the kidney. We recently showed that leptin is necessary for fibrosis to develop in the liver and that increased levels of leptin increases the severity of liver fibrosis. It appears that leptin is a fundamental player in the biological processes of hepatic fibrosis. As increased serum levels of leptin is a feature of obesity, leptin is likely to be the missing link between obesity and increased hepatic fibrosis. By understanding the mechanisms by which leptin acts on liver cells to increase fibrosis, this work will lead to new strategies to prevent fibrosis in obese patients and to reverse scarring in the liver. With the endemic obesification in developed countries, prevention and treatment of obesity-associated liver disease will be the main challenge for the hepatologist in the next decades.Read moreRead less
Protein Tyrosine Phosphatases, Cellular Signaling & Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$727,685.00
Summary
Protein tyrosine phosphatases (PTPs) control cell communication networks referred to as cellular signaling. This proposal is focused on understanding the roles of PTPs in cellular signaling networks perturbed in human disease & delineating novel opportunities for therapeutic intervention.
Cardiovascular Effects Of Enhanced Leptin Signalling
Funder
National Health and Medical Research Council
Funding Amount
$1,200,972.00
Summary
Leptin treatment causes weight loss, but leptin also increases blood pressure. We wish to determine if increasing leptin signalling, by modifying signal transduction pathways within leptin sensitive cells in the brain, can reduce weight without increasing blood pressure.
Molecular Mechanisms Underlying The Positive Associations Between Male Gender And Leptin With Barretts Oesophagus
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
Barrett's oesophagus is a disease of the gullet that can lead to the development of oesophageal cancer, which has a very poor outcome. We have shown that the risk of Barrett's oesophagus is greatest in obese males with a high blood level of leptin, a hormone made in fat tissue. The aim of this study is to examine how leptin causes this increased cancer risk, so that new treatments or tests for Barrett's and oesophageal cancer can be developed.
Novel Actions Of Leptin In Implantation And Placental Function
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
The establishment, growth and function of the placenta is of critical importance to the successful maintenance and completion of pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes and coordination of hormone signals that regulate fetal growth and development. Among these signals the hormone leptin, which is produced primarily by fat cells and regulates food intake, has been identified as a crucial player in the control of f ....The establishment, growth and function of the placenta is of critical importance to the successful maintenance and completion of pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes and coordination of hormone signals that regulate fetal growth and development. Among these signals the hormone leptin, which is produced primarily by fat cells and regulates food intake, has been identified as a crucial player in the control of fetal growth. In human pregnancy, the placenta becomes an additional major source of leptin, and this is secreted into the mother and the fetus. Recent work in animal models also indicates that the process of implantation, whereby the embryo embeds itself in the lining of the uterus and establishes a placenta, cannot proceed in the absence of leptin. But how leptin exerts these critical effects on the implantation process and placental function is not known. In this study we will explore several potential actions of leptin in the uterus and placenta, and examine whether the leptin signaling system is aberrant in cases where the fetus does not grow normally. Of particular interest is the possible interaction of leptin with another group of important signaling molecules called the peroxisome proliferator-activated receptors, or PPARs. One of these, PPAR-gamma, plays an indispensable role in the establishment of the placenta, particularly in relation to the formation of blood vessels, a process that is also a target for leptin action. Several lines of evidence, most notably in fat cells, suggest that both PPAR-gamma and leptin regulate common aspects of cell function. Such interactions provide us with important clues as to how leptin and the PPARs could work together to promote the optimal establishment, growth and function of the placenta, and these will be explored in this project.Read moreRead less