IL22 signaling in epilepsy

癫痫发生是将正常脑转变为癫痫脑的病理过程，通常 由基因突变和神经损伤如癫痫持续状态（SE）引发。存在未满足的需求 因为癫痫几乎无法预防。引发的脑部炎症 神经元损伤越来越多地被认为是癫痫发生的一个因素。小胶质细胞，一般认为 作为常驻巨噬细胞，在癫痫性损伤和思维时高度增殖和激活。 发挥主要作用。除了常驻的小胶质细胞外，外周系统和CNS中的其他免疫细胞 淋巴系统也浸润CNS隔室，并可能导致癫痫发生。还有待 了解中枢神经系统常驻和非常驻免疫细胞如何相互作用，以响应致癫痫性损伤， 损伤引发的免疫网络变化如何影响非免疫细胞，如星形胶质细胞， 神经元，从而有助于癫痫发生。这一提议是基于我们的观察，即IL 22 R α1是 在颞叶癫痫的毛果芸香碱模型中，星形胶质细胞中的表达强烈上调。这种诱导依赖于 关于脑部炎症此外，IL 22 R α1的诱导与星形胶质细胞增生密切相关， 癫痫患者脑内星形胶质细胞的增殖和活化。这些发现导致我们的中央 假设IL 22/IL 22 R α1信号上调促进星形胶质细胞增殖，这反过来 会导致癫痫提出了三个具体目标来检验我们的假设。目标1将决定 星形胶质细胞IL 22 R α1表达上调的机制目的2将阐明产生IL 22的免疫细胞 被募集到中枢神经系统区室。目的3将确定阻断IL 22信号传导是否能减弱星形胶质细胞增生 并改变癫痫发生的过程。我们的研究不仅将提高我们对IL 22 信号调节癫痫发生，但也可以确定药物靶点，以防止癫痫发生。

Epileptogenesis is a pathological process that transforms a normal brain into an epileptic brain, typically initiated by genetic mutations and neurological insults such as status epilepticus (SE). There is an unmet need to understand epileptogenesis because it remains nearly unpreventable. Brain inflammation triggered by neuronal injury is increasingly recognized as a contributor to epileptogenesis. Microglia, generally considered as resident macrophages, are highly proliferated and activated in response to epileptogenic insults and thought to play a primary role. Besides resident microglia, other immune cells in the peripheral system and CNS lymphatic system also infiltrate the CNS compartment and likely contribute to epileptogenesis. It remains to be understood how CNS resident and non-resident immune cells interact in response to epileptogenic insults and how the injury-triggered changes in the immune network impinge on non-immune cells such as astrocytes and neurons, thereby contributing to epileptogenesis. This proposal is built on our observation that IL22Rα1 is strongly up-regulated in astrocytes in the pilocarpine model of temporal lobe epilepsy. This induction depends on brain inflammation. Moreover, the induction of IL22Rα1 is critically involved in astrogliosis, an excessive proliferation and activation of astrocytes frequently seen in epileptic brains. These findings lead to our central hypothesis, that up-regulation of IL22/IL22Rα1 signaling promotes astrocyte proliferation, which in turn contributes to epileptogenesis. Three specific aims are proposed to test our hypothesis. Aim 1 will determine how IL22Rα1 expression is up-regulated in astrocytes. Aim 2 will elucidate how IL22-producing immune cells are recruited into the CNS compartment. Aim 3 will determine if blocking IL22 signaling attenuates astrogliosis and modifies the process of epileptogenesis. Our study will not only improve our understanding how IL22 signaling regulates epileptogenesis, but could also identify druggable targets to prevent epileptogenesis.