Increasing Functional Liver Mass in Health and Disease

描述（由申请人提供）： 中毒性损伤后或切除后肝再生失败将导致死亡。目前的治疗选择是支持性治疗或肝移植。尽管对实验性肝再生的机制进行了数十年的深入研究，但不存在增强再生反应的疗法。对肝再生机制的研究发现，正常的静息肝脏对生长刺激是不敏感的。然而，一旦损伤，生长因子、信号分子和细胞周期蛋白的许多复杂级联协调肝细胞从生长停滞（GO）退出，进入细胞周期（G1），DNA合成和有丝分裂，并最终停止生长。还鉴定了对抑制细胞凋亡和调节对氧化损伤的反应重要的分子。损伤后肝再生失败的机制基础和内在性肝病的影响正逐渐被阐明。我们的长期目标是将这些知识转化为肝脏疾病的治疗，并填补对再生过程的理解中的重要空白。最近，我们已经表明，持续的，高剂量的IL-6单独全身给药的结果在大规模的肝细胞增殖和肝脏生长在未受伤的小鼠通过直接诱导增殖和抑制细胞凋亡。 我们的假设是（1）高剂量IL-6的施用可用于围手术期以改善肝损伤并增强再生，以及（2）传统生长因子（如HCF）和强直性生长抑制剂（如卵泡抑素）的抑制剂可与IL-6协同作用以促进肝生长，减少所需的IL-6的剂量和持续时间，从而最小化毒副作用，同时最大化肝生长。（2）的基础是HGF和卵泡抑素通过彼此不同且与IL-6不同的途径刺激肝细胞增殖，表明增加肝脏生长的相加或协同潜力。 具体目标： (1)确定在高风险肝脏手术环境中围手术期给予高剂量IL-6改善肝损伤和促进肝再生的程度和机制。 (2)确定HCF和卵泡抑素沿着与IL-6共同给药促进肝脏生长反应和降低IL-6相关毒性的程度和机制。

DESCRIPTION (provided by applicant): 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.