Clonal Proliferation Of Hepatocytes And Progression Of Liver Disease In Chronic Hepatitis B Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$420,558.00
Summary
Infection with the hepatitis B virus (HBV) can lead to either acute resolving, or chronic HBV infection. Chronic HBV infections are often associated with severe liver disease, and increased risk of liver cancer and occur worldwide in 350 million people. HBV infects hepatocytes, the major cell of the liver. Early during infection 100% of hepatocytes are infected. However, this percentage declines over time to 10-50% or less. The reasons for this are unknown. We suggest that changes in the liver c ....Infection with the hepatitis B virus (HBV) can lead to either acute resolving, or chronic HBV infection. Chronic HBV infections are often associated with severe liver disease, and increased risk of liver cancer and occur worldwide in 350 million people. HBV infects hepatocytes, the major cell of the liver. Early during infection 100% of hepatocytes are infected. However, this percentage declines over time to 10-50% or less. The reasons for this are unknown. We suggest that changes in the liver cell population occur because of the immune response against infected hepatocytes. We hypothesize that the immune response kills infected hepatocytes and provides and growth advantage to hepatocytes that can no longer be infected with HBV. This leads to the clonal proliferation of HBV-negative hepatocytes that over time become the major cell population in the liver. We will study human liver tissue using molecular techniques to detect the HBV DNA that integrates randomly into cell DNA during HBV infection. We will then determine the copy number of specific integrated virus-cell junctions as a measure of hepatocyte proliferation. Sections of fixed liver will also be examined for changes in histology and frequency of HBV infection. These studies will determine if foci of HBV-negative hepatocytes are clonal. This finding would suggest that a major role of the immune system in the development of liver cancer is to restrict the genetic pool of hepatocytes. We hypothesise that liver cancer beings with a very specific survival advantage for hepatocytes that lack HBV replication and antigen expression, and that proliferation of these cells expands the pool of potentially altered HCC precursor cells.Read moreRead less
Though vaccination has had a major impact on the number of persons becoming infected, chronic infection with the hepatitis B virus (HBV) still remains a major worldwide problem, with 350 million people chronically infected. The existence of HBV vaccine escape mutants and the fact that 5% of vaccinees fail to respond implies that HBV will remain a significant public health problem for the foreseeable future. Current treatments for chronic HBV infection have a low success rate (~20%) and patients ....Though vaccination has had a major impact on the number of persons becoming infected, chronic infection with the hepatitis B virus (HBV) still remains a major worldwide problem, with 350 million people chronically infected. The existence of HBV vaccine escape mutants and the fact that 5% of vaccinees fail to respond implies that HBV will remain a significant public health problem for the foreseeable future. Current treatments for chronic HBV infection have a low success rate (~20%) and patients with chronic infection are expected to die prematurely due to chronic liver disease or primary liver cancer. Interestingly, exposure to HBV can lead to either acute resolving or chronic HBV infection. Like chronic infections, acute infections involve spread of virus to virtually every hepatocyte, followed by rapid clearance of the virus mediated by the host immune response. Our immediate aim is to study the resolution of acute HBV infections to determine how the stable intracellular viral genome, covalently closed circular DNA (cccDNA), is cleared from the nucleus of infected hepatocytes. Our broad long-term aim is to develop new and effective treatments for chronic HBV infection based on a better understanding of how acute HBV infections are resolved by the host. Based on our previous work we believe that clearance of cccDNA requires hepatocyte death, together with compensatory proliferation of other infected hepatocytes. We will perform detailed studies in duck hepatitis B virus (DHBV) infected ducks to determine if hepatocyte death and compensatory proliferation are essential to clear the infection, or if mechanisms exist for clearance that do not involve cell destruction.Read moreRead less
The Predictors Of Prostate Cancer In The Melbourne Collaborative Cohort Study
Funder
National Health and Medical Research Council
Funding Amount
$358,457.00
Summary
In 1990 we set up a long-term study of diet and health. The aim was to measure diet and other risk factors in healthy people in order to see how they might affect future development of cancer. To do this we recruited 41,500 people aged 40 to 69, measured what they ate and drank, and collected information on other aspects of lifestyle, medical history, and family history of common diseases. All had height and weight and blood pressure measured and gave a blood sample. People were selected so that ....In 1990 we set up a long-term study of diet and health. The aim was to measure diet and other risk factors in healthy people in order to see how they might affect future development of cancer. To do this we recruited 41,500 people aged 40 to 69, measured what they ate and drank, and collected information on other aspects of lifestyle, medical history, and family history of common diseases. All had height and weight and blood pressure measured and gave a blood sample. People were selected so that men and women and migrants from Italy and Greece would be included. In this way we could widen the range of dietary habits, other lifestyle factors and genetic variation (measured in DNA from blood). Since then participants have completed another questionnaire and instances of disease have been noted from self reports and from examining medical records. We want to analyse data from 700 men in the study who have developed prostate cancer (PC). First we will analyse data collected on all 17,000 men (collected when joining the study, and at follow up). Next we will use data from only the 700 men with PC and 1400 men who have not developed PC. This study will focus on measuring substances in the blood. We want to measure a range of fats, vitamins, antioxidants and phytoestrogens, as well as male sex hormones and related substances. In the DNA from the blood we plan to measure variations in genes that influence how male sex hormones and other growth factors important in the prostate are produced and used. We will then be able to estimate what affect these factors have on the risk of getting PC. We will also be able to see if any of them act together to make the risk of PC much higher in certain men. This work should identify what lifestyle factors could reduce the risk of PC. It should also identify what genetic variations are associated with increased risk of PC and thus identify a sub group of men who might benefit from early medical attention or from changes in lifestyle.Read moreRead less