T cell immunity in a rare juvenile form of motor neuron disease

项目总结 肌萎缩侧索硬化症(ALS)是最常见的运动神经元病(MND)。 一些报告强调了一些致病基因和免疫力之间的联系。 系统。然而，免疫细胞是否以及如何在特定形式的ALS中对MND起作用 还没有定义。 肌萎缩侧索硬化症4(ALS4)是一种罕见的青少年MND，由基因突变引起 编码核解旋酶的基因Senataxin(SETX)普遍表达我们的 被确定为炎症反应的转录调节因子的组。 通过使用ALS4的小鼠模型，我们发现造血系统对 神经退行性变过程。此外，我们还发现，中枢神经系统中的CD8 T细胞和 受疾病影响的小鼠和患者的外周血被异常激活。我们的目标是 明确CD8 T细胞在疾病发生和发展中的作用。我们将确定其功能 疾病相关CD8 T细胞的转移和耗竭实验及免疫组织学研究 在小鼠身上的特征(目标1)。我们将评估神经免疫的分子途径 转录和相关结构的网络模型在疾病过程中的相互作用 分析(目标2)。最后，我们将在小鼠模型中验证激活的CD8T细胞的存在 和其他形式的肌萎缩侧索硬化症患者(目标3)。我们的 贡献 的 结果将使我们更深入地了解 CD8 T细胞在肌萎缩侧索硬化症中的表达及其作为免疫生物标志物的可能途径 疾病进展和作为新的治疗靶点。

PROJECT SUMMARY Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor neuron disease (MND). Several reports have highlighted a link between some disease-causing genes and the immune system. However, whether and how immune cells contribute to MND in specific forms of ALS is yet to be defined. Amyotrophic Lateral Sclerosis 4 (ALS4) is a rare and juvenile MND caused by mutations in the gene SENATAXIN (SETX), which encodes for a nuclear helicase ubiquitously expressed that our group identified as a transcriptional regulator of inflammatory response. By using a mouse model of ALS4, we found that the hematopoietic system contributes to the neurodegenerative process. Additionally, we discovered that CD8 T cells in the CNS and the peripheral blood of disease-affected mice and patients are aberrantly activated. Our goal is to define the role of CD8 T cells in disease initiation and progression. We will determine the function of disease-associated CD8 T cells by transfer and depletion experiments and immune-histological characterization in mice (Aim 1). We will assess molecular pathways of neuro-immune interactions during disease by network modeling of transcriptomic and correlation-structure analyses (Aim 2). Finally, we will validate the presence of activated CD8 T cells in mouse models and patients with other forms of ALS (Aim 3). Our contribution of results will provide a deeper knowledge of the of CD8 T cells in ALS and open potential avenues for their use as immune biomarkers disease progression and as novel therapeutic target.