IL22 signaling in epilepsy

癫痫发生是一个将正常大脑转变为癫痫大脑的病理过程，通常 由基因突变和神经侮辱引发，如癫痫持续状态(SE)。有一种未得到满足的需求 理解癫痫的发生，因为它几乎是无法预防的。由以下因素引发的脑部炎症 神经元损伤越来越被认为是癫痫发生的一个因素。小胶质细胞，通常被认为 作为常驻巨噬细胞，在致痫的侮辱和思想的反应中高度增殖和激活 发挥主要作用。除了驻留的小胶质细胞外，周围系统和中枢神经系统中的其他免疫细胞 淋巴系统也渗入中枢神经系统，可能与癫痫的发生有关。它还有待于 了解中枢神经系统常驻和非常驻免疫细胞如何相互作用，以应对致痫侮辱和 损伤引发的免疫网络变化如何影响非免疫细胞，如星形胶质细胞和 神经元，从而促进癫痫的发生。这一建议是建立在我们观察到的IL22Rα1是 在匹罗卡品的颞叶癫痫模型中，星形胶质细胞表达强烈上调。这种归纳法取决于 关于脑部炎症的研究。此外，IL22Rα1的诱导与星形胶质细胞增生症密切相关，这是一种过度的 癫痫脑中常见的星形胶质细胞的增殖和激活。这些发现导致了我们的中央 假设IL22/IL22Rα1信号上调促进星形胶质细胞增殖，进而 有助于癫痫的发生。为了检验我们的假设，本文提出了三个具体目标。目标一号将决定 IL-22Rα-1在星形胶质细胞中的表达上调Aim 2将阐明产生IL22的免疫细胞如何 被招募到中枢神经系统的隔间里。AIM 3将确定阻断IL22信号是否减轻星形胶质细胞增生症 并改变癫痫的发生过程。我们的研究不仅将提高我们对IL22如何 信号调节癫痫的发生，但也可以确定预防癫痫发生的可用药靶点。

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.