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Regulation Of Liver Iron Loading In Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$663,188.00
Summary
Hereditary haemochromatosis is a common iron overload disorder. It affects 1 in 200 Australians causing liver iron overload, fibrosis, cirrhosis and cancer. The severity of liver iron overload in haemochromatosis is variable. In this study we will determine whether factors that are known to regulate iron metabolism such as iron levels, oxidative stress and inflammation modify liver iron transport systems and the degree of liver iron loading in animal models of haemochromatosis.
Non-alcoholic steato-hepatitis (NASH) is a common disease of liver inflammation and scarring, which may progress to cirrhosis or liver cancer. While type 2 diabetes causes a higher rate of NASH and more rapid NASH progression the reasons for this are not clear. We have developed a novel animal model of NASH with diabetes added to dietary induced obesity. We show that a growth factor is elevated in the affected livers. We plan to block the growth factor to see if we can prevent NASH worsening.
Altered Hepatic Pharmacokinetics As A Consequence Of Drug- And Disease-induced Changes In Hepatic Vascularity.
Funder
National Health and Medical Research Council
Funding Amount
$498,088.00
Summary
Many drugs are broken down by the liver or are removed from the liver out into the intestine by the bile, as well as being removed by the kidney and other organs. The effectiveness of the breakdown and removal by the liver depends both on whether the drug can get into the liver cells and on how well the enzymes in the liver are working. Cardiovascular and liver diseases and certain drugs can affect both of these processes. This work is concentrating on those processes which mainly affect the upt ....Many drugs are broken down by the liver or are removed from the liver out into the intestine by the bile, as well as being removed by the kidney and other organs. The effectiveness of the breakdown and removal by the liver depends both on whether the drug can get into the liver cells and on how well the enzymes in the liver are working. Cardiovascular and liver diseases and certain drugs can affect both of these processes. This work is concentrating on those processes which mainly affect the uptake process. The diseases of most interest are liver cirrhosis, fatty liver disease, atherosclerosis and chronic heart failure, all of which together are leading causes of death in Western countries. They are also associated with liver dysfunction due to effects on liver vessels. We have a poor understanding of how the effects of these diseases and a number of drugs on liver vessels affect the functioning of the liver, especially in terms of how they affect drug breakdown or removal of drugs. This project seeks to understand these effects and proposes a number of animal studies as well as human studies to provide insight. The drugs to be studied are those most commonly used in patients with cardiovascular and liver diseases, as one of our main goals is to provide better therapeutic management in these patients.Read moreRead less
Liver damage after liver surgery or shock is called ischemia-reperfusion injury (IRI). Recovery after surgical removal of liver tissue is due to liver regeneration. IRI and liver regeneration are controlled by specialised proteins called cytokines, one of which, TRAIL, is essential for both IRI and liver regeneration. This research is to find out how TRAIL exerts such seemingly opposite effects. The aim is to learn how to protect the liver against damage, and to stimulate its recovery.
MECHANISTIC ROLE OF CHOLESTEROL IN NON-ALCOHOLIC STEATOHEPATITIS
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
Fatty liver is present in 15-30% of Australians, related to obesity, diabetes and heart attack. Two-thirds of cases reverse easily. The remainder evolve to non-alcoholic steatohepatitis (NASH), liver damage that can lead to cirrhosis and liver failure. This research seeks to find out why some cases of fatty liver lead to NASH, and whether cholesterol that accumulates in the livers of mice with NASH is what causes that damage. If so, we will find new ways to treat NASH by diet or drugs.
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
Preconditioning: The Molecular Basis For Protection From Hepatic Ischemia-reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
When the blood supply to the liver is cut off temporarily (ischemia) and later restored (reperfusion) the liver is damaged by a process called ischemia-reperfusion (IR) injury. This is a major problem during liver surgery and is also an underlying problem in liver transplantation; following storage of a donor liver ready for placing into the recipient it can undergo a similar process called preservation injury. We now understand a lot about how IR comes about, particularly by the formation of da ....When the blood supply to the liver is cut off temporarily (ischemia) and later restored (reperfusion) the liver is damaged by a process called ischemia-reperfusion (IR) injury. This is a major problem during liver surgery and is also an underlying problem in liver transplantation; following storage of a donor liver ready for placing into the recipient it can undergo a similar process called preservation injury. We now understand a lot about how IR comes about, particularly by the formation of damaging oxygen radicals within liver cells to start a process of programmed cell death, but it remains difficult to prevent or treat IR injury. A recent breakthrough has been recognition that subjecting the liver to only a short period (5 or 10 minutes) of ischemia protects against a later period of prolonged ischemia or IR. In the investigator s mouse model, for example, such preconditioning was 60 to 90% protective (depending on the time after IR). This project seeks to understand how preconditioning works to protect the liver against IR injury. Our idea is that preconditioning generates a limited amount of oxygen radicals, and that these turn on signalling pathways in the cell that regulate certain protective genes. Genes that encode antioxidant and other anti-stress pathways are likely to be important, but so are genes that prepare the cell to enter the cell cycle and divide into new cells that regenerate the liver. Conversely, genes that program cell death may be turned off. The outcomes of this research will be to understand the molecular and cellular basis of how preconditioning protects against ischemia-reperfusion injury of the liver. This will allow drug treatments to be devised that, by simulating preconditioning, prevent this common and severe type of liver damage.Read moreRead less
Pathogenesis Of Liver Injury And Hepatic Fibrosis In Non-Alcoholic SteatoHepatitis, NASH
Funder
National Health and Medical Research Council
Funding Amount
$438,055.00
Summary
Nonalcoholic steatohepatitis (NASH) is the most common form of liver disease in affluent countries. In Australia at least 3% of the population and 20% of those with obesity have NASH. This poorly understood disease covers a spectrum of liver disorders - from relatively benign presence of excess fat in the liver - to cirrhosis and liver failure. This pattern of liver damage is virtually identical to alcoholic hepatitis, however alcohol consumption is excluded in NASH. It is often associated with ....Nonalcoholic steatohepatitis (NASH) is the most common form of liver disease in affluent countries. In Australia at least 3% of the population and 20% of those with obesity have NASH. This poorly understood disease covers a spectrum of liver disorders - from relatively benign presence of excess fat in the liver - to cirrhosis and liver failure. This pattern of liver damage is virtually identical to alcoholic hepatitis, however alcohol consumption is excluded in NASH. It is often associated with type II diabetes , obesity and lipid disorders. Although fatty liver by itself is thought to be innocuous and reversible, a small number of cases with this mild syndrome progress to a more severe form of NASH. One aim of this project is to identify and characterise the factors which trigger injury in a fatty liver and lead to the destruction of liver cells. In response to the initial liver injury in NASH, cells in the liver and from the immune system mount an inflammatory reaction. However this may make the liver even more susceptible to further injury by amplifying the effect of the initial insult. The inflammatory response is controlled by key signalling molecules produced by specific liver and immune cells. The second aim of this project is to identify such molecules and their cellular source and to determine whether they perpetuate the disease processes of NASH. One outcome of liver injury and the consequent inflammatory reaction is that the liver repairs the damage by forming fibres of scar tissue in a process similar to wound healing. When unchecked this process of fibrosis leads to cirrhosis and the development of severe liver complications. The final aim is to gain new insights into the links between liver cell injury, the inflammatory response and fibrosis which will eventually lead to treatments to prevent the initial triggers of this disease and also to interrupt the progression of NASH to more serious fibrotic stage.Read moreRead less
The Role Of CYP2E1 In Ethanol-mediated Protein Damage And Its Impact On Proteolytic Processing In The ER
Funder
National Health and Medical Research Council
Funding Amount
$179,239.00
Summary
Alcoholic liver disease (ALD) is the primary factor leading to mortality in chronic alcohol abusers. Alcoholic patients possess antibodies to damaged proteins in their bloodstreams, which indicates an underlying level of oxidative damage is occurring in their livers. The antibodies to these damaged proteins could trigger the destruction of liver cells. Alternatively, the damaged proteins themselves could result in cell death because of the way they are degraded in a particular compartment of the ....Alcoholic liver disease (ALD) is the primary factor leading to mortality in chronic alcohol abusers. Alcoholic patients possess antibodies to damaged proteins in their bloodstreams, which indicates an underlying level of oxidative damage is occurring in their livers. The antibodies to these damaged proteins could trigger the destruction of liver cells. Alternatively, the damaged proteins themselves could result in cell death because of the way they are degraded in a particular compartment of the cell, the endoplasmic reticulum (ER). An enzyme, CYP2E1, has been demonstrated to produce the types of chemicals that damage proteins and it is significantly increased in the liver by alcohol consumption. The current scientific proposal is aimed at determining whether CYP2E1 induction by ethanol contributes to ALD by perturbing the normal cellular disposal of damaged proteins in the ER.Read moreRead less