肝脏缺血再灌注损伤与肝脏再生的补体依赖性机制与调控研究

Activation of the complement descries associated with both ischemia reperfusion injury (IRI) and liver regeneration (liver repair) with complement playing both an injurious role and a reparative role. However, the precise complement dependent mechanisms involved in liver injury/repair are not well defined. Since complement inhibitory strategies used to protect IRI will probably result in impairment of liver regeneration, this pose a significant clinical challenge. We spearheaded the development of a program to study the role of complement in liver injury and regeneration. Our preliminary studies highlight the important divergent roles of complement in IRI and liver regeneration. Based on our novel findings, the general goal of this proposal is to understand the role of complement in liver injury and repair and determine the therapeutic efficacy of complement inhibition. Our working hypothesis is that complement plays dual roles in liver injury and repair, not only playing a key role in promoting injury, but also having important functions in sparing liver regeneration. However, excessive and aggravated activation of the complement system, which occurred in most clinic cases , is implicated in both injury and the impairment of liver repair and our targeted complement inhibitory strategies may prove an effective treatment option, not only for amelioration of injury but also in promoting liver repair. We hypothesize that a balanced or timed approach of complement inhibition, or the selective inhibition at certain points in the complement pathway, will provide effective therapeutic benefit in most clinic cases. Especially, “Energy Crisis”, a potential mechanism responsible for complement related liver regeneration impairment, suggests energy supply make our complement inhibitory strategies more safe and effective. Our aim is to better define the complement dependent mechanisms involved in hepatic injury and liver repair, and depending on the role of complement in injury vs regeneration.

激活后的补体系统在肝脏损伤与修复过程中扮演双刃剑角色：既参与肝脏缺血再灌注损伤（Ischemia reperfusion injury,IRI）又为启动肝脏再生所必需，减轻肝脏IRI的补体抑制方案可能导致肝脏再生障碍，无疑是亟待解答的临床挑战。我们前期工作中发现：补体的过度激活阻碍肝脏再生，通过平衡过度激活的补体能够显著改善肝再生。基于前期新发现进一步提出工作假设：尽管补体具有参与损伤和启动修复的双重作用，但过度激活的补体（临床常见）既参与IRI又阻碍肝脏再生，恰当的补体抑制不仅减轻IRI也改善肝脏再生；早期补体信号为肝脏再生必需，而后期补体成分对肝再生影响较小，特别是补体终末产物膜攻击复合物则可能起到关键性致伤作用，分割性补体通路调控研究有利于筛选更合理的调控靶点；补体水平不足可能通过“能量危机”参与再生障碍，能量补偿方案值得期待。项目旨在探索减轻肝脏损伤促进肝再生的精准补体调节策略。

激活后的补体系统在肝脏损伤与修复过程中扮演双刃剑角色：既参与肝脏缺血再灌注损伤 （Ischemia reperfusion injury,IRI）又为启动肝脏再生所必需，减轻肝脏IRI的补体抑制方案可能导致肝脏再生障碍，无疑是亟待解答的临床挑战。我们前期工作中发现：补体的过度激活阻碍肝脏再生，通过平衡过度激活的补体能够显著改善肝再生。基于前期新发现进一步提出工作假设：尽管补体具有参与损伤和启动修复的双重作用，但过度激活的补体（临床常见）既参与IRI又阻碍肝脏再生，恰当的补体抑制不仅减轻IRI也改善肝脏再生；早期补体信号为肝脏再生必需，而后期补体成分对肝再生影响较小，特别是补体终末产物膜攻击复合物则可能起到关键性致伤作用，分割性补体通路调控研究有利于筛选更合理的调控靶点；补体水平不足可能通过“能量危机”参与再生障碍，能量补偿方案值得期待。本项目通过小鼠肝脏IRI模型、部分肝切除模型以及不同补体基因缺陷小鼠和系列靶向性补体抑制剂系统探索了肝脏缺血再灌注损伤与肝脏再生的补体依赖性机制与调控策略，提出了“分割性补体调控”创新策略，着重探讨了“能量危机”工作假说，有望为临床减轻肝脏损伤与改善肝脏修复提供新的精准补体干预靶点和策略。相关研究在Cell Res和Front Immunol等杂志发表SCI论文10篇；获授权专利6项，其中发明专利4项；获得广西科学技术奖特别贡献类特等奖、广西自然科学奖二等奖、中国产学研合作创新成果奖一等奖及中国发明创业奖·创新奖一等奖各1项；培养研究生17名。