IL22 Signaling in Epilepsy

癫痫中的 IL22 信号传导

基本信息

批准号：
10548133
负责人：
Yunfei Huang
金额：
$ 40.83万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548133
关键词：
Address Antibodies Astrocytes Atopic Dermatitis Attenuated Biological Products Brain Cell Communication Cells Characteristics Clinical Trials DNA Sequence Alteration Disease Encephalitis Epilepsy Epileptogenesis Etiology Goals Homeostasis Human Immune Immunohistochemistry Immunologics Individual Infection Infiltration Inflammatory Injections Injury Interleukin-1 beta Lead Lymphoid Cell Macrophage Mediating Meninges Microglia Modeling Mus Neurologic Neuronal Injury Neurons Pathologic Pathologic Processes Peripheral Phase II Clinical Trials Pilocarpine Play Process Proliferating Reaction Regulation Reporter Role Safety Signal Transduction Status Epilepticus Surface System T-Lymphocyte TNF gene Temporal Lobe Epilepsy Testing Translating Up-Regulation Western Blotting astrogliosis brain parenchyma combat cytokine druggable target glymphatic system immunoreaction improved insight interleukin-22 mouse model neuronal excitability neutralizing antibody new therapeutic target novel preclinical study prevent receptor recruit response response to injury tissue repair

项目摘要

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.

癫痫发生是一种病理过程，将正常大脑转化为癫痫大脑，通常是由遗传突变和神经系统侮辱（例如癫痫症（SE））发起。有未满足的需求了解癫痫发生，因为它几乎无法预防。脑部炎症触发神经元损伤越来越多地被认为是癫痫发生的贡献者。小胶质细胞，通常考虑由于居民巨噬细胞，对癫痫发作的响应高度增殖并激活扮演主要角色。除居民小胶质细胞外，外周系统和中枢神经系统中的其他免疫细胞淋巴系统还渗入中枢神经系统室，并可能有助于癫痫发生。还有了解中枢神经系统居民和非居民免疫小球如何响应癫痫发作和伤害触发了免疫网络中的变化，影响了星形胶质细胞等非免疫细胞的变化神经元，从而导致癫痫发生。该提议建立在我们观察到IL22Rα1是临时叶癫痫的毛果果模型中的星形胶质细胞中强烈上调。这种诱导取决于关于脑注射。此外，IL22Rα1的诱导与星形胶质细胞增多症密切相关，过量星形胶质细胞的增殖和激活经常在癫痫大脑中看到。这些发现导致了我们的中心假设，IL22/IL22Rα1信号的上调促进了星形胶质细胞增殖有助于癫痫发生。提出了三个特定目标来检验我们的假设。 AIM 1将确定在星形胶质细胞中如何上调IL22Rα1的表达。 AIM 2将阐明如何产生IL22的免疫细胞被招募到中枢神经系统车厢中。 AIM 3将确定阻塞IL22信号是否会减弱星形胶质细胞增多症并修饰癫痫发生的过程。我们的研究不仅会改善我们的理解如何IL22 信号传导调节癫痫生成，但也可以鉴定可预防癫痫发生的可吸毒靶标。