HMGB1-TLR4信号通路在角膜移植排斥中的作用及分子机制研究

角膜移植排斥（CGR）是角膜移植失败的主要原因，治疗棘手。巨噬细胞（Mф）是器官移植排斥的主要效应细胞。我们前期研究表明，HMGB1/TLR4（简称HT）信号通路在CGR中发挥重要作用。最近<Nature>报道Caspase 8-caspase3/7-NF-κB（简称CCN）是TLR4激活中枢神经Mф的重要下游信号通路，而我们前期研究也证明HMGB1可在体外通过活化Mф的TLR4调控此通路，促进炎症因子释放。因此我们推测：内源性HMGB1激活MФ的TLR4，从而诱导CGR；HT通路可能通过调控CCN通路，促进CGR的发生、发展；靶向阻断HMGB1-TLR4- Caspase 8--caspase 3/7-NF-κB（简称HT-CCN）可抑制CGR。本课题拟通过基因敲除等方法靶向阻断HT-CCN通路，明确这一通路在CGR的发展和治疗中的作用，为器官移植排斥提供新的药物治疗靶点。

Corneal graft rejection（CGR), a main reason for the failure of corneal transplantation, is still a therapeutic challenge for ophthalmologists. Macrophages (Mф) are the main inflammatory cells in CGR. Our preliminary studies show that HMGB1/TLR4 (HT) pathway played key roles in CGR. "Nature" recently reported that Caspase 8-caspase3/7-NF-κB(CCN) is key downstream signaling in TLR4-mediated Mф activation in the central nervous system(CNS). Furthermore, our preliminary studies demonstrated that CCN is involved in HT-mediated macrophages activation and inflammatory cytokines production in vitro.Thus,we speculate that HT-CCN pathway may is crucial for the development of CGR and targeting blockade of HT-CCN pathway may inhibit CGR. It is expected that this study can further elucidated the mechanism of CGR and explore a new clinical therapeutic approach for CGR.