Characterization of Proteases in Biliary Atresia-AssociatedLiver Cirrhosis

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Biliary atresia (BA) is the single most important disease leading to liver cirrhosis in children. Despite initial successful correction of BA by using Kasai』s procedure, liver fibrosis still progresses in most cases. Repeated postoperative cholangitis may explain the phenomenon in some of the cases. But for the most patients, the exact etiology is unknown. Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) are the key enzymes responsible for degradation and deposition of all the protein components of extracellular matrix and the basement membrane. There are 24 human MMPs and four naturally occurring TIMPs. A few MMPs such as MMP-1, MMP-2, MMP-9 and MMP-13, and TIMP-1, TIMP-2 and TIMP-3 have been studied in BA, alcoholic liver fibrosis, chronic hepatitis C and liver fibrosis secondary to Schistosoma mansoni infection as well to other hepatobiliary disorders20, 21. The results from these studies are inconsistent and sometimes controversial, which are obviously affected by their underlying diseases. Many more MMPs are unknown as to their roles in the pathogenesis of liver fibrosis/cirrhosis. We have used cDNA microarray to characterize cytokine expression profiles in different stages of BA and to compare it with the normal control. Some of the results, particularly in terms of MMPs, are a little different from a recent report by others. This proposal is designed to characterize the 10 MMPs and 4 TIMPs obtained from the array. Although the scale is not large enough to cover all the 24 MMPs, the proposal still contains the largest number of MMPs to date to study the liver fibrosis due to BA. In order to limit the budget, only those genes that show a difference in signal intensity (in DNA microarray) greater than 2-fold between groups will be further quantified with the use of real-time quantitative RT-PCR. Further characterization with the use of in situ hybridization and immunohistochemistry is limited to one or two genes that show greatest difference in transcript between groups. This study may help to identify major proteases or their inhibitors that are involved in the progress of liver fibrosis in BA. A strategy to decrease liver fibrosis based on the findings is anticipated. Based on our preliminary results, MMP-7 may well be the candidate genes that play the most important role in liver fibrogenesis. Although mentioned in two recent articles using cDNA microarray to study BA, MMP-7 has not been characterized in BA. It is worthwhile to study this protease as well as some other potentially important MMPs or TIMPs in fibrogenesis associated with BA.

Project IDs

Project ID:PC9308-0984
External Project ID:NSC93-2314-B182-054
StatusFinished
Effective start/end date01/08/0431/07/05

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