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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
American Liver Foundation Postdoctoral Research Fellowship Award
Boston University School of Medicine, Boston, Massachusetts
“Mechanisms of Hepatic Adhesion Formation”
Although partial hepatectomy (PHx) is one of effective treatment for hepatocellular carcinoma (HCC) and metastatic colorectal cancer (mCRC), it invariably results in the formation of hepatic adhesions which often cause postoperative complications. Additionally, the aforementioned adhesions make secondary PHx much riskier should HCC and mCRC recur. Even though hepatic adhesion is a serious problem, there have been no studies concerning the underlying adhesion mechanism in parenchymal organs, and as a result there are currently no approved therapies for their prevention. The goal of Dr. Kosaka’s research project is therefore to fully elucidate the cytokine pathways that lead to hepatic adhesion following PHx, with emphasis on those that regulate fibrinolytic system.
Dr. Kosaka’s newly established “mouse PHx-adhesion model” can induce reproducible hepatic adhesions in mice at 7 days. The severity of adhesions is evaluated by using well established scoring system. BALB/c, wild type (WT) mice will be compared to two strains of knockout mice: IFN-gamma (IFN-γ)-deficient and Natural Killer T (NKT) cell-deficient. In addition, WT mice will be treated with respective blocking antibodies or recombinant hepatocyte growth factor (HGF). Immunohistochemistry will be used to assess NKT cell accumulation into the residual liver. Real time PCR will be used to assess the mRNA expression of cytokines and chemokines of interest, and protein levels will be measured by ELISA. Peritoneal fibrinolytic activity will be measured using an assay developed in his laboratory.
The contribution of CD4 +T cells, especially NKT cells, to hepatic adhesions will be established. The dynamics of IFN-γ, PAI-1 and some chemokines following PHx will be revealed at the mRNA expression and protein level. NKT cell driven IFN-γ will be defined as indispensable factor for hepatic adhesions. Namely, IFN-γ will strongly increase both mRNA expression and protein level of PAI-1. HGF will be identified as a useful preventive factor of hepatic adhesions via its regulation of both IFN-γ and PAI-1.
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