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

一种罕见的青少年运动神经元疾病中的 T 细胞免疫

• 批准号: 10595316
• 负责人: Laura Campisi
• 金额: $ 65.97万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595316
• 关键词: ALS pathology; ALS2 gene; Adaptive Immune System; Adolescent; Adoptive Transfer; Affect; Amyotrophic Lateral Sclerosis; Animal Testing; Antigens; Autoimmune Process; Autoimmunity; Big Data; Biological Markers; Blood; Bone Marrow Transplantation; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Central Nervous System; Cessation of life; Clinical Management; Clonal Expansion; Cortical Cord; DNA; Data; Disease; Disease Progression; Epigenetic Process; Etiology; Frequencies; Functional disorder; Genes; Genetic Transcription; Genetic Variation; Goals; Hematological Disease; Hematopoietic System; Histologic; Histology; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunologic Markers; Immunologics; Immunophenotyping; Immunotherapy; Inflammatory Response; Knock-in; Knock-in Mouse; Knockout Mice; Knowledge; Link; Memory; Modeling; Molecular; Motor Cortex; Motor Neuron Disease; Motor Neurons; Mus; Mutation; Nerve Degeneration; Neuroglia; Neuroimmune; Neurons; Nuclear; Pathologic; Pathology; Pathway interactions; Patients; Play; Population; Population Analysis; Process; Proteins; RNA Helicase; Reporting; Research; Research Project Grants; Resolution; Role; Sampling; Spinal Cord; Structure; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Variant; autosomal dominant mutation; autosome; behavior test; behavioral impairment; cell type; diagnostic biomarker; disease-causing mutation; experimental study; fused in sarcoma; helicase; human model; knockin animal; mouse model; network models; neuroimmunology; new therapeutic target; novel; peripheral blood; programs; progressive neurodegeneration; response; transcriptomics

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.

项目概要 肌萎缩侧索硬化症 (ALS) 是运动神经元疾病 (MND) 最常见的形式。 一些报告强调了一些致病基因与免疫系统之间的联系 系统。然而，在特定形式的 ALS 中，免疫细胞是否以及如何促进 MND 尚不清楚。 尚待定义。 肌萎缩侧索硬化症 4 (ALS4) 是一种罕见的青少年 MND，由肌萎缩侧索硬化症 (ALS4) 突变引起 基因 SENATAXIN (SETX)，编码普遍表达的核解旋酶 组被确定为炎症反应的转录调节因子。 通过使用 ALS4 小鼠模型，我们发现造血系统有助于 神经退行性过程。此外，我们发现中枢神经系统和神经系统中的 CD8 T 细胞 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 定义 CD8 T 细胞在疾病发生和进展中的作用。我们将确定函数 通过转移和耗竭实验以及免疫组织学研究与疾病相关的 CD8 T 细胞 小鼠表征（目标 1）。我们将评估神经免疫的分子途径 通过转录组和相关结构的网络建模在疾病期间相互作用 分析（目标 2）。最后，我们将验证小鼠模型中激活的 CD8 T 细胞的存在 以及患有其他形式的 ALS 的患者（目标 3）。我们的 贡献 的 结果将提供更深入的了解 CD8 T 细胞在 ALS 中的作用，并为其用作免疫生物标志物开辟了潜在途径 疾病进展并作为新的治疗靶点。