Hepatic Fibrogenesis In Paediatric Cholestatic Liver Disease.
Funder
National Health and Medical Research Council
Funding Amount
$254,250.00
Summary
Liver disease in children causes a significant impact on lifespan and quality of life. The commonest causes of liver disease in children are cholestatic, or diseases related to obstruction of bile flow out of the liver. In ways we are only beginning to understand, obstruction of bile flow stimulates liver scar formation which, if untreated, leads to replacement of normal liver tissue and ultimately to failure of the liver. In infants, the most common and serious cholestatic liver disease is bili ....Liver disease in children causes a significant impact on lifespan and quality of life. The commonest causes of liver disease in children are cholestatic, or diseases related to obstruction of bile flow out of the liver. In ways we are only beginning to understand, obstruction of bile flow stimulates liver scar formation which, if untreated, leads to replacement of normal liver tissue and ultimately to failure of the liver. In infants, the most common and serious cholestatic liver disease is biliary atresia. It develops at, or shortly after birth with progressive destruction of the bile ducts, responsible for transporting bile out of the liver. Without early diagnosis and surgery these infants develop progressive liver scarring leading to liver failure and death or liver transplantation within 1-2 years. It is the commonest reason for liver transplantation in children (55-60%) in the Western world. Even with successful surgery, most, if not all patients will come to liver transplantation over the subsequent 25 years because of ongoing, but slower, scar formation. In older children, diseases like cystic fibrosis cause bile duct blockages leading to progressive liver scarring that is slower and unpredictable, contributing to ill health in up to 20% of patients and death from end stage liver disease or liver transplantation in 5%. Using liver tissue from children with these two disorders we have been able to identify the key cells that control the liver scar process, the Hepatic Stellate Cell. We now need to investigate the role of bile constituents on the scar-forming process in these two diseases. We will utilise a well characterised animal model to investigate the influence of bile constituents on cells isolated from this model and apply these findings back to patient samples to determine their role in paediatric cholestatic liver disease. This will help us to better understand the disease process and importantly, develop more effective and earlier treatment.Read moreRead less
Previous research has shown that SIDS victims have a number of subtle abnormalities that set them apart from the normal population. These include the occurrence of upper airway obstruction in sleep, a reduced ability to awaken from sleep and abnormalities of the automatic control of heart rate and blood pressure in sleep. These body functions are controlled by a component of the brain called the autonomic nervous system which controls the heart and other internal functions by means of nerves cal ....Previous research has shown that SIDS victims have a number of subtle abnormalities that set them apart from the normal population. These include the occurrence of upper airway obstruction in sleep, a reduced ability to awaken from sleep and abnormalities of the automatic control of heart rate and blood pressure in sleep. These body functions are controlled by a component of the brain called the autonomic nervous system which controls the heart and other internal functions by means of nerves called the parasymmpathetic and sympathetic systems. The purpose of this project is to undertake studies of the autonomic system in normal infants and in those infants who are considered to be at risk for SIDS. As SIDS occurs almost exclusively in sleep it is important to study the infant?s heart rate and blood pressure responses to various challenges whilst asleep. All infants (both controls and subjects) enrolled in the protocol will therefore undergo overnight sleep studies during which their automatic responses to a variety of stimuli will be measured. Once we have established the normal response to these stimuli we can then compare them to the results of the at risk group. If, as we anticipate, there is a difference between our at risk group and the normal controls in automatic function then we will measure some of the stress hormones in the body which reflect the function of the autonomic nervous system. If there is a difference in the levels of these hormones between the normal and the at risk groups which correlates with the expected subtle abnormalities in function we may be able to devise an accessible and quantifiable measure for those infants at risk of SIDSRead moreRead less