Does Immunosuppression Affect The Post-transplantation Hepatic Fibrogenic Response?
Funder
National Health and Medical Research Council
Funding Amount
$360,000.00
Summary
Liver transplantation is often the only treatment option for patients who progress to end-stage liver disease after initial treatment has failed. Unfortunately, re-emergence of disease is common and patients often develop fibrosis and cirrhosis (scarring of the liver) in the donor organ. In some cases it has been observed that this scarring often develops rapidly, sometimes in a year or less following transplantation. Re-transplantation is often required. This differs from the usual progression ....Liver transplantation is often the only treatment option for patients who progress to end-stage liver disease after initial treatment has failed. Unfortunately, re-emergence of disease is common and patients often develop fibrosis and cirrhosis (scarring of the liver) in the donor organ. In some cases it has been observed that this scarring often develops rapidly, sometimes in a year or less following transplantation. Re-transplantation is often required. This differs from the usual progression of cirrhosis pre-transplant which often takes years or decades to develop. While essential to prevent rejection of the transplanted organ, immunosuppression is not without side effects. To date, few studies have examined the effect of immunosuppressive agents on the development of hepatic fibrosis and the key fibrosis effector cell type, the hepatic stellate cell. These reports have shown that one of the most commonly used immunosuppressant agents (FK-506) may adversely influence fibrosis progression while rapamycin may prevent fibrosis progression. However little is known regarding the mechanisms through which this occurs. We propose to examine the effect of four different immunosuppressants on fibrosis development both in vitro and in vivo to determine whether scar development or scar breakdown pathways are altered post-immunosuppression. If the factors driving the fibrogenesis in the transplanted organ can be elucidated it may then be possible to develop therapeutic strategies to tackle the problem. This may result in a reduced need for re-transplantation which has obvious benefits to the transplant patient but would also reduce the numbers of donor organs required.Read moreRead less
Microparticles In NASH: Origins, Pathogenic Roles, And Biomarker Of Disease Activity
Funder
National Health and Medical Research Council
Funding Amount
$540,633.00
Summary
30% of Australians have non-alcoholic fatty liver disease (NAFLD). Cirrhosis is the third cause of death; only 10-25% of NAFLD livers show steatohepatitis (NASH), which leads to cirrhosis. We have found that microparticles (MPs), small fragments of cell membranes, circulate in NASH but not in ordinary fatty liver. We will now explore ways in which MPs incite inflammation and liver fibrosis in NASH, and design new tests based on MPs to improve clinical assessment of patients with NAFLD/NASH.
Novel Vasoactive Pathways In Liver Disease; Experimental And Clinical Studies
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
Cirrhosis of the liver due to chronic hepatitis and other common liver diseases is now a major cause of illness and death in Australia. This project will examine how a hormone system called the renin angiotensin system contributes to the development of liver damage in these diseases. We will study whether drugs targeting this system can be used to reduce liver scarring and prevent the development of cirrhosis and its complications.
Mechanisms Underlying Growth, Lineage Commitment And Differentiation Of Liver Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
Liver disease is a serious health problem. Viral hepatitis, obesity and alcohol can result in end-stage liver disease. Organ transplant is the only treatment available. A widening gap between organ donations and recipients mandates alternative treatments are developed. Cell transplantation and artificial liver devices are alternatives which can use liver progenitor cells. We will investigate how factors grow and convert them into liver cells for treating liver disease patients.
ALCOHOL AND IMPAIRED LIVER REGENERATION: EFFECTS ON MITOGENIC SIGNALING PATHWAYS
Funder
National Health and Medical Research Council
Funding Amount
$365,295.00
Summary
Patients who regularly consume alcohol are slow to recover from liver injury because alcohol poisons the liver's capacity to regenerate itself (grow back). Hence patients with alcohol-induced liver disease have a high mortality and prolonged hospital stays. The applicants have been supported by NHMRC to study how alcohol impairs liver regeneration. They found that the effect is at the level of cell surface receptors for the growth factors that control liver regeneration. Alcohol alters the funct ....Patients who regularly consume alcohol are slow to recover from liver injury because alcohol poisons the liver's capacity to regenerate itself (grow back). Hence patients with alcohol-induced liver disease have a high mortality and prolonged hospital stays. The applicants have been supported by NHMRC to study how alcohol impairs liver regeneration. They found that the effect is at the level of cell surface receptors for the growth factors that control liver regeneration. Alcohol alters the function of these receptors. One major discovery has been that it damages the capacity to generate a rise in calcium within the cell, something that is fundamentally required for any cell to divide and reproduce itself. Thus when a rise in calcium was produced artificially (with chemicals to unlock the internal calcium stores), liver cells from alcohol-fed rats once more responded normally under the influence of growth factors and replicated themselves. The present work isdesigned to find out where this effect of calcium is exerted. The investigators believe that it is related to how other types of signals work, the so-called protein kinase pathways. These are cascades of one protein turning on (activating) the next down the line to ultimately switch on the genes that control cell growth. They will manipulate liver cells from alcohol-fed rats in culture to establish which of these pathways is most affected, and which is the most critical for the control of cell division genes. These studies will greatly advance our understanding about how alcohol impairs liver regeneration. They will give new insight into the control of liver cell growth and division that is such a crucial response of the liver to injury, vital for survival of the liver. This kind of knowledge will open the door for new treatments to be designed that can control liver growth - turn it back on when it has been poisoned, or turn it off when it is inappropriately vigorous and predisposing to liver cancer.Read moreRead less
Role Of Human Amnion Epithelial Cells In Resolving Hepatic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$618,755.00
Summary
When the liver is injured repeatedly by viruses and alcohol, it responds through a wound healing process that can lead to extensive scar tissue in the liver (cirrhosis). This condition may require liver transplantation and lifelong use of drugs to prevent the body from rejecting the new organ. To develop an alternate therapy, we will study if substances secreted by amnion cells from the human placenta (afterbirth), which would normally be discarded, can reduce liver scar tissue in mice .