Hepatocyte Replicative Arrest, Hepatic Progenitor Cells And The Ductular Reaction In Hepatic Fibrogenesis
Funder
National Health and Medical Research Council
Funding Amount
$527,683.00
Summary
Chronic liver diseases such as hepatitis C and obesity-related fatty liver can be associated with scarring that eventually results in cirrhosis and liver failure. We are unsure why this scarring occurs, but as hepatitis and fatty liver are becoming more common it is necessary to understand this process so that effective therapies can be developed. This study looks at one possible mechanism to explain the development of liver scarring. We believe that the normal repair mechanisms of the liver lea ....Chronic liver diseases such as hepatitis C and obesity-related fatty liver can be associated with scarring that eventually results in cirrhosis and liver failure. We are unsure why this scarring occurs, but as hepatitis and fatty liver are becoming more common it is necessary to understand this process so that effective therapies can be developed. This study looks at one possible mechanism to explain the development of liver scarring. We believe that the normal repair mechanisms of the liver lead to the production of liver cells to replace those that have died, but in some circumstances also produce small bile ducts that drain bile from the hepatocytes. These small bile ducts may have a previously unsuspected role in stimulating the scar formation. The study will see if the small bile ducts are produced in a range of liver diseases in humans, and will use rodent models to find the factors responsible for stimulating the scarring. When the process is understood more clearly, it could lead to the development of new or more effective therapies to reduce or even reverse liver scarring.Read moreRead less
MOLECULAR AND CELLULAR PATHOGENESIS OF HUMAN LIVER DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$4,928,323.00
Summary
n humans, chronic liver diseases cause cirrhosis of the liver in some but not all individuals. This leads to protracted ill-health, complications (fluid retention in the abdomen, confusion, bloodstream infections, kidney failure, liver cancer) resulting in hospitalisation, liver transplantation and premature death. In Australia, cirrhosis is an important cause of death and of years of potential life lost, while liver cancer has recently doubled and is predicted to treble by 2020. The common caus ....n humans, chronic liver diseases cause cirrhosis of the liver in some but not all individuals. This leads to protracted ill-health, complications (fluid retention in the abdomen, confusion, bloodstream infections, kidney failure, liver cancer) resulting in hospitalisation, liver transplantation and premature death. In Australia, cirrhosis is an important cause of death and of years of potential life lost, while liver cancer has recently doubled and is predicted to treble by 2020. The common causes are hepatitis C, fatty liver disorders, alcohol and hepatitis B; when 2 of these are present together, there is a higher risk of cirrhosis. This program aims to unravel the pathological processes which cause cirrhosis at the molecular and cellular levels, in order to understand why some people are at higher risk. These processes could result from genetic predisposition, other constitutional factors (age, gender) or from lifestyle factors (overnutrition, inactivity, alcohol). The 3 chief investigators from Westmead s Millennium Institute and the Centenary Institute of Royal Prince Alfred Hospital are international experts in hepatitis C, non-alcoholic steatohepatitis (NASH) and other fatty liver disorders, autoimmune hepatitis, liver transplantation, and scarring processes that lead to cirrhosis of the liver. The new knowledge that will result from these studies will be used to help prevent people developing severe forms of chronic liver disease, and for treating cirrhosis if it has already occurred.Read moreRead less
Role Of Nuclear Receptors In Hepatic Injury And Fibrogenesis
Funder
National Health and Medical Research Council
Funding Amount
$443,520.00
Summary
Chronic liver disease is a major cause of death and ill health on a word-wide scale. Several common liver diseases, such as hepatitis B, hepatitis C and non-alcoholic steatohepatitis (fatty liver disease not due to alcohol), are capable of causing protracted liver damage. Irrespective of the cause of injury, the liver has a very narrow way of responding to chronic damage. The most important and insidious of these is hepatic fibrosis (scarring), which, along with liver regeneration, eventually le ....Chronic liver disease is a major cause of death and ill health on a word-wide scale. Several common liver diseases, such as hepatitis B, hepatitis C and non-alcoholic steatohepatitis (fatty liver disease not due to alcohol), are capable of causing protracted liver damage. Irrespective of the cause of injury, the liver has a very narrow way of responding to chronic damage. The most important and insidious of these is hepatic fibrosis (scarring), which, along with liver regeneration, eventually leads to cirrhosis if the injurious process is sufficiently intense and sustained. Liver cirrhosis is the precursor to several undesirable complications of liver disease, most notably primary liver cancer (also called hepatoma), liver failure and severe bleeding from the gut. Therefore, it is not surprising that effective strategies to control liver injury and prevent cirrhosis have been called the holy grail of liver research. To date the only therapies for substantially improving the outcome of patients with chronic liver disease are those that halt or remove the cause of injury. Unfortunately, in many cases it is still not possible to remove or effectively treat the cause of injury. Because of this there is intense interest in therapies that might favourably alter the response of the liver to injury and especially in those that may retard or inhibit scarring and prevent cirrhosis. Nuclear receptors are sensors that control many aspects of the body's metabolism, especially the metabolism of cholesterol and fat. Recently, our work and that of others has suggested that some nuclear receptors may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so, and which of the several nuclear receptors likely to be involved are the important ones. We will then extend these studies to see if drugs that activate these receptors will improve or prevent severe liver disease.Read moreRead less