Programme(s) to which this project applies:
|☒ MPhil/PhD||☑ MRes[Med]||☒ URIS|
Objective and Significance:
Orthotopic liver transplantation (OLT) has been regarded as the best curative treatment for the patients with end stage of liver diseases including advanced liver cirrhosis and acute liver failure. Because of the severe shortage of grafts from brain-death donors and the importance of timely operation on recipients, living donor liver transplantation (LDLT) offers the unique opportunity of early transplantation with theoretically unlimited source of liver grafts. Since the first successful adult to adult LDLT in Hong Kong in 1994, this surgical innovation has been well established locally and relived the organ donor shortage. However, a liver graft from a living donor is frequently small-for-size for the recipient. To expand the potential liver donor pool, "marginal" liver grafts are hence often utilized. Grafts are considered marginal if there is an increased risk of initial poor function or primary nonfunction. Steatosis is the most common reason used to classify a donor liver as marginal. Acute phase fatty graft injury after transplantation will deteriorate when the graft is small-forsize, such as a partial liver graft from a live donor. Such acute phase liver grafts injury will not only trigger a series of inflammatory cascades, but also may inhibit hepatocyte regeneration, activate liver progenitor cell proliferation/differentiation and subsequently lead to chronic liver disease (such as recurrence of biliary liver fibrosis) of the marginal graft. Therefore, understanding the molecular response controlling the activation and expansion of the hepatic progenitor cell niche and the microenvironments orchestrating regeneration by recruitment of progenitor cells in marginal liver grafts will be crucial to prevent early graft non-function/inhibition of liver regeneration and the development of chronic liver damage, such as liver biliary cirrhosis after liver transplantation. In the proposed study, we intend to investigate the distinct regeneration pattern and precise molecular mechanism of marginal liver graft after transplantation. A rat orthotopic liver transplantation model using small-for-size fatty graft and the recipient with cirrhotic liver will be applied to mimic LDLT using fatty graft. The liver regeneration pattern including the proliferation of hepatocytes and progenitor/oval cells, and chronic liver graft injury such as biliary cirrhosis will be compared between the small-for-size fatty liver graft and small-forsize normal graft. The potential molecular signature linking to distinct regeneration pattern of small- for-size fatty graft will be identified. In vivo functional studies will be carried out in the specific gene deficient mice to explore the possible mechanisms. The direct role of target genes leading to inhibition of hepatocyte regeneration and promotion of progenitor cell proliferation/differentiation will be further confirmed in a series of in vitro experiments.
Elucidating the precise molecular mechanism of liver regeneration of marginal graft will lay the foundation for the further development of therapeutic strategies to prevent graft nonfunction and late phase graft cirrhosis. Investigation of potential novel treatments in animal models will provide important information for future clinical application, especially in LDLT using fatty liver grafts. It will also open a new window for the Research & Development for local and overseas pharmaceutical companies. Therefore, there will also have potential commercial benefit for the R&D industries.
Research Plan and Methodology:
The study consists of four phases, focusing on the investigation of the regeneration pattern of marginal liver grafts and further exploration of underlying precise molecular mechanism. In the first phase, a rat liver transplantation model using small-for-size fatty graft and cirrhotic recipient will be established. The distinct regeneration pattern of small-for-size fatty liver graft will be investigated. In the second phase, the underlying molecular mechanisms of distinct regeneration pattern of marginal grafts will be explored. The specific molecular signature leading to progenitor/oval cell activation/proliferation/differentiation and graft fibrosis will be identified. In the third phase, in vivo functional studies will be further carried out using the specific gene deficient mice to verify the direct roles of these genes on bile duct injury (EMT) and subs quent liver fibrosis of marginal grafts. A series of in vitro functional studies will also be conducted. In the fourth phase, in vivo and in vitro studies will be conducted to investigate the role of progenitor cells/oval cells on tumor recurrence and metastasis.
Remark: the candidates for Master of Research in Medicine will join the parts of this ongoing
Professor K Man, Department of Surgery
Professor Nancy K Man is currently the Director of Liver Transplantation and Liver Cancer Research, and Director of Clinical and Translational Research in Department of Surgery, The University of Hong Kong. She is well-recognized for the advancements of liver transplantation research. Her innovative development and successful application of integrated clinical, translational and basic research for liver graft injury and cancer recurrence after transplantation, has resulted in major advances and impact on transplant oncology and immunology.Biography
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