TLR介导的炎症信号在脑海绵状血管畸形（CCM）发病过程中的作用机理

脑海绵状血管畸形（CCM）是一种自发性或家族性的脑血管疾病，能引起脑出血，中风和神经功能缺失。人类遗传研究已经证实CCM1，CCM2或CCM3的功能缺失性突变会导致CCM疾病。 在新生小鼠中诱导CCM1，CCM2，CCM3基因敲除能导致CCM病灶的形成，这一动物模型很好地模拟了人类CCM疾病。我们发现了CCM蛋白复合物是MEKK3激酶系列的抑制因子。CCM基因的缺失导致MEKK3激酶系列的活化并促进了下游基因的表达。我们用遗传学方法在小鼠模型中证明了降低MEKK3/KLF信号可以预防CCM的形成。因此在CCM发病过程中MEKK3的活化是关键环节。 发现确认MEKK3激酶的活化信号对CCM发病机理和疾病治疗有重要意义。 我们最近的工作证实革兰氏阴性杆菌和LPS可以通过TLR4促进CCM疾病发生。在这一项目中，我们将通过体内体外实验来阐明:TLR介导的炎症信号驱动MEKK3激酶诱发CCM疾病。

Cerebral cavernous malformations (CCMs) are sporadic or inherited vascular malformations in the brain with a prevalence of 0.1~0.5% in the human population. Loss of function mutations in three genes, CCM1, CCM2 and CCM3, have been identified as causing human familial CCMs. CCM1, CCM2, and CCM3 encode cytosolic adaptor proteins and form a single signaling complex. We found CCM protein complex is suppressive factor of MEKK3 kinase cascade. Deletion of CCM genes leads to activation of MEKK3 kinase cascade and increased expression of downstream targets such as KLF2/4, Adamts4/5. We have also further confirmed that MEKK3/KLF/Adamts signaling is upregulated in human CCM lesions, and genetically decrease MEKK3/KLF signal can prevent CCM lesion formation in mouse models. Therefore the activation of MEKK3/KLF is a critical step in CCM lesion initiation. Identify the activating signal for MEKK3 kinase cascade has significant therapeutic application. Using a recently emerged sub-colony of resistant CCM model, we identified bacterial infection and LPS can promote CCM formation. Deletion of TLR4 inhibits CCM lesion formation in susceptible CCM model. This proposal will investigate how TLR mediated inflammatory signaling interacts with CCM pathway to promote CCM lesion formation.