申请者在前期发现了一组以星形细胞抗体为标记的罕见疾病，GFAP可能是该抗体的靶抗原。临床与病理学证实它与犬的肉芽肿性脑膜脑脊髓炎高度相似。星形细胞GFAP的脱失、凋亡和自噬现象亦被证实。动物实验证实GFAP抗体具有损伤星形细胞的效应。我们提出假设：GFAP在疾病中起关键作用，GFAP抗体-抗原轴调控下游相关信号通路、介导星形细胞损伤与炎症发生发展。因此，本项目拟开展研究:(1)建立基于GFAP表达的分子预测模型，评价这一指标的临床适用价值；(2)敲除鼠GFAP基因,证实星形细胞抗体的唯一靶点是GFAP；(3)建立基于GFAP抗体诱导的细胞与动物模型，通过控制GFAP表达对模型炎症反应的影响来阐明GFAP在疾病发生、进展中的关键作用；(4)根据前期工作的基础，阐明在GFAP抗体作用下，GFAP是否通过Akt信号通路调控、影响星形细胞凋亡与自噬。本项目对该疾病的临床与基础研究均具有重要意义。

Autoimmune-inflammatory diseases in central nervous system (CNS) represent a broad spectrum, including monophasic, multiphasic, and progressive disorders and ranging from highly localized forms to multifocal or diffuse variants. Human common CNS autoimmune-inflammatory diseases, including multiple sclerosis and neuromyelitis optica disorder spectrum have been well known as autoantibody-independent astrocytopathy. However, another rare astrocytopathy with specific antibody, targeting to glial fibrillary acidic protein (GFAP), are still poorly understood due to limited studies. Since June 2013, we have encountered some rare cases with a pattern-specific astrocyte-antibody in CSF and/or serum. This antibody is targeting to the glial fibrillary acidic protein (GFAP). The clinical and pathological data were certified that such cases were highly similar to granulomatous meningoencephalomyelitis (GME) in animals. Loss of GFAP in astrocyte, apoptosis and autophahgy in astrocyte were found in our previous study. Animal study showed a pathogenic role of GFAP antibody to the astrocyte. A scientific hypothesis was raised in our present project that astrocyte injury and inflammatory response in GME is associated with signal pathway regulated by GFAP antigen and its antibody. GFAP is critical to pathogenesis of GME. Therefore, study will be performed in the present project, including: (1) clinical value of GFAP will be elevated; (2) we will clarify that GFAP is the sole antigen to astrocyte-antibody by gene knockout technology;(3) a critical role to pathogenesis of GFAP will be certified by cell and animal model; (4)based on our previous result, we will explore astrocyte apoptosis and autophagy in Akt signal pathway, which is controlled by GFAP antigen- GFAP antibody response. Our project is helpful for clinical and basic study of GME in the future.