Increasing Functional Liver Mass in Health and Disease

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Failure of liver regeneration after toxic injury or after resection will result in death. Current treatment options are supportive therapy or liver transplantation. Despite decades of intensive investigation into the mechanisms of experimental liver regeneration no therapies to augment the regenerative response exist. Research into the mechanism of liver regeneration have found that normal resting liver is refractory to growth stimuli. Once injured, however, many complex cascades of growth factors, signaling molecules and cell cycle proteins orchestrate the coordinated exit of hepatocytes from growth arrest (GO), into the cell cycle (G1), DNA synthesis and mitosis, and finally cessation of growth. Molecules important for suppression of apoptosis and regulation of the response to oxidative injury have also been identified. Increasingly, the mechanistic bases for the failure of liver regeneration after injury and the effects of intrinsic liver disease are being illuminated. Our long-term goal is to translate such knowledge to the treatment of liver disease and to fill essential gaps in the understanding of the process of regeneration. Recently we have shown that systemic administration of sustained, high-dose IL-6 alone results in massive hepatocyte proliferation and liver growth in uninjured mice through direct induction of proliferation and suppression of apoptosis. Our hypothesis is (1) administration of high-dose IL-6 can be used peri-operatively to ameliorate liver injury and augment regeneration and (2) tradtional growth factors, such as HCF, and inhibitors of tonic growth repressors, such as Follistatin, may synergize with IL-6 to promote liver growth, reducing the dosage and duration of IL-6 required, thereby minimizing toxic side effects while maximizing liver growth. The basis for (2) is that HGF and Follistatin stimulate hepatocyte proliferation through pathways distinct from each other and from IL-6, suggesting additive or synergistic potential for increasing liver growth. Specific Aims: (1) Determine the extent to which and mechanisms by which high-dose IL-6 ameliorates liver injury and facilitates liver regeneration when administered peri-operatively in the setting of high-risk liver surgery. (2) Determine the extent to which and mechanisms by which co-administrating HCF and Follistatin along with IL-6 facilitates the liver growth response and reduces IL-6 associated toxicity.
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