Role of CSF microglia in health and disease

小胶质细胞是中枢神经系统(CNS)卵黄囊来源的长寿、自我复制的免疫细胞。 实质是免疫和神经病理的关键调节器。小胶质细胞功能障碍导致 与退伍军人事务部相关的几种神经系统疾病，包括多发性硬化症(MS)和肌萎缩侧索硬化症 硬化症(ALS)。在我们的初步研究中，我们意外地发现了循环中的小胶质细胞 MS和ALS患者的脑脊液(CSF)。我们假设脑脊液小胶质细胞是内源性的。 表现出神经系统疾病状态特有特征的中枢神经系统细胞。我们的目标是识别任何疾病- 脑脊液小胶质细胞的相关特征。我们将探索脑脊液的数量和免疫学特征 流式细胞仪分析MS和ALS中的小胶质细胞。探讨脑脊液小胶质细胞的分子特征 对于各种疾病状态，我们将对分选的细胞进行单细胞RNA测序。我们将进行比较 MS和ALS患者脑脊液小胶质细胞基因表达谱差异及与健康对照的关系 受试者以确定这些细胞的健康和疾病特异性图谱。最后，我们将追求流量 大鼠的细胞学和RNA测序研究，特别关注MS和ALS的模型，以揭示 脑脊液小胶质细胞的起源和功能。这项提议将为描述一个 具有调节中枢神经系统免疫功能的新型细胞群。

Microglia are long-lived, self-replicating, yolk sac-derived immune cells of the central nervous system (CNS) parenchyma that are critical modulators of immunity and neuropathology. Microglia dysfunction contributes to several neurologic diseases relevant to the VA, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). In our preliminary studies, we have unexpectedly identified microglia circulating with the cerebrospinal fluid (CSF) of patients with MS and ALS. We hypothesize that CSF microglia are endogenous CNS cells that exhibit signatures unique to neurologic disease states. We aim to identify any disease- associated characteristics of CSF microglia. We will explore the number and immunologic features of CSF microglia in MS and ALS by flow cytometric analysis. To explore the molecular signature of CSF microglia in various disease states, we will perform single cell RNA sequencing on sorted cells. Comparisons will be made between gene expression patterns in CSF microglia between MS and ALS and in relation to healthy control subjects to determine the health- and disease-specific profile of these cells. Finally, we will pursue flow cytometric and RNA sequencing studies in rats, with a particular focus on models of MS and ALS, to uncover the origins and function of CSF microglia. This proposal will lay the groundwork for the characterization of a novel cellular population capable of regulating CNS immunity.