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IL22 signaling in epilepsy

癫痫中的 IL22 信号传导

基本信息

批准号：
10320485
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/10320485
关键词：
Address Antibodies Astrocytes Atopic Dermatitis Attenuated Biological Products Brain Cells Characteristics Clinical Trials DNA Sequence Alteration Disease Encephalitis Epilepsy Epileptogenesis Etiology Goals Homeostasis Human Immune Immunohistochemistry Immunologics Individual Infection Inflammatory Injections Injury Interleukin-1 beta Lead Lymphoid Cell 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 macrophage 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.

癫痫发生是正常大脑转变为癫痫大脑的病理过程，通常是由基因突变和神经损伤（例如癫痫持续状态（SE））引发。有一个未满足的需求了解癫痫的发生，因为它仍然几乎是不可预防的。引发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，会高度增殖并激活以应对致癫痫的侮辱和思想发挥主要作用。除了常驻小胶质细胞外，外周系统和中枢神经系统中的其他免疫细胞淋巴系统也浸润中枢神经系统，可能导致癫痫发生。仍有待了解中枢神经系统驻留和非驻留免疫细胞如何相互作用以应对致癫痫的损伤损伤引发的免疫网络变化如何影响星形胶质细胞等非免疫细胞神经元，从而促进癫痫发生。该提议基于我们的观察，即 IL22Rα1 是在颞叶癫痫的毛果芸香碱模型中星形胶质细胞中强烈上调。这个归纳取决于关于大脑炎症。此外，IL22Rα1 的诱导与星形胶质细胞增生（一种过度的胶质细胞增生）密切相关。星形胶质细胞的增殖和激活常见于癫痫脑中。这些发现导致我们的中心假设，IL22/IL22Rα1 信号传导的上调可促进星形胶质细胞增殖，进而促进星形胶质细胞增殖有助于癫痫发生。提出了三个具体目标来检验我们的假设。目标1将决定 IL22Rα1 表达如何在星形胶质细胞中上调。目标 2 将阐明产生 IL22 的免疫细胞如何被招募到中枢神经系统室。目标 3 将确定阻断 IL22 信号传导是否会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 IL22 如何发挥作用的理解信号传导调节癫痫发生，但也可以识别可药物靶点以预防癫痫发生。