JAML负调控SIRT1激活小胶质细胞在颅咽管瘤下丘脑非可控炎症损伤的机制探究

釉质型颅咽管瘤（ACP）导致的下丘脑功能障碍严重危害患者的生存质量。申请者前期实验发现：ACP毗邻的下丘脑区域内普遍存在非可控性炎症引发的神经损伤；ACP囊液内脂类物质可诱导小胶质细胞高表达JAML介导非可控性炎症的产生。进一步转录测序、生信分析，提示：上调的JAML可下调小胶质细胞SIRT1表达并抑制其促炎反应。据此，申请者提出以下假说：ACP囊液内脂类物质诱导ACP毗邻小胶质细胞高表达JAML，后者通过负性调控SIRT1表达以增加NF-κB的乙酰化，继而抑制非可控性炎症的负反馈，最终导致下丘脑神经损伤。本课题拟在前期工作基础上，通过干预JAML/SIRT1表达，并构建JAML基因敲除鼠、立体定向下丘脑囊液注射模型以及侧脑室胶囊泵注入SIRT1激动剂等手段，确证JAML/SIRT1对小胶质细胞非可控性炎症的调控及其导致下丘脑神经损伤的机制，为ACP导致的下丘脑功能障碍提供新的防治靶点。

Hypothalamic dysfunction caused by adamantinomatous craniopharyngioma (ACP) seriously damages life quality of ACP patients. Previous experiments of the applicant found that nerve injury caused by nonresolving inflammation was common in the hypothalamus adjacent to the ACP and lipids in ACP cyst fluid could induce high expression of JAML in microglia and mediate nonresolving inflammation. Further transcriptional sequencing and bioinformatics analysis suggested that up-regulated JAML could down-regulate the expression of SIRT1 in microglia and inhibit its pro-inflammatory response. Accordingly, the applicant proposed the following hypothesis: lipids in ACP cyst fluid induced high expression of JAML in ACP adjacent microglia, which negatively regulated the expression of SIRT1 to increase the acetylation of NF-κB, and then inhibited the negative feedback of nonresolving inflammation, eventually resulting in hypothalamic nerve injury. On the basis of previous work, by interfering with JAML/SIRT1 expression, constructing JAML gene knockout mice, stereotactic hypothalamic cystic fluid injection model and injecting SIRT1 agonist into lateral ventricle with capsule pump, this study confirmed the regulation of JAML/SIRT1 on microglial nonresolving inflammation and the mechanism of hypothalamic nerve injury, and provided a new target for prevention and treatment of hypothalamic dysfunction caused by ACP.