Role of CSF microglia in health and disease

脑脊液小胶质细胞在健康和疾病中的作用

• 批准号: 10367573
• 负责人: Gregory Wu
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367573
• 关键词: Address; Amyotrophic Lateral Sclerosis; Animal Model; Biological Assay; Biopsy; Bone Marrow; Cell Separation; Cell physiology; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Characteristics; Chimera organism; Dendritic Cells; Disease; Elements; Exhibits; Exposure to; Flow Cytometry; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Growth; Health; Human; Immune; Immunity; Immunologic Markers; Immunologics; Individual; Inflammation; Informatics; Investigation; Membrane Proteins; Microglia; Modeling; Molecular; Molecular Profiling; Multiple Sclerosis; Mutation; Myelogenous; Myeloid Cells; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurology; Pathogenesis; Patients; Phenotype; Population; Primary Progressive Multiple Sclerosis; Process; Property; Radiation; Rattus; Resolution; Role; Sampling Studies; Source; Sum; Techniques; Tissues; Traction; Yolk Sac; base; cerebrospinal fluid flow; differential expression; efficacious treatment; insight; monocyte; multiple sclerosis patient; nervous system disorder; neuroinflammation; neuropathology; new therapeutic target; next generation; next generation sequencing; novel; patient stratification; prognostic; prospective; protein expression; single-cell RNA sequencing; superoxide dismutase 1; therapeutic development; trait; transcriptome sequencing; transcriptomics

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.

小胶质细胞是中枢神经系统（CNS）的长寿、自我复制、卵黄囊衍生的免疫细胞 是免疫和神经病理学的关键调节剂。小胶质细胞功能障碍有助于 与VA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（ALS）。 硬化症（ALS）。在我们的初步研究中，我们出乎意料地发现了小胶质细胞循环与 MS和ALS患者的脑脊液（CSF）。我们假设CSF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CNS细胞。我们的目标是找出任何疾病- CSF小胶质细胞的相关特征。我们将探讨脑脊液中阳性细胞的数量和免疫学特征 MS和ALS中的小胶质细胞通过流式细胞术分析。探索脑脊髓灰质炎患者CSF小胶质细胞的分子特征 在各种疾病状态下，我们将对分选的细胞进行单细胞RNA测序。将进行比较 MS和ALS之间CSF小胶质细胞的基因表达模式之间的关系以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特征。最后，我们将追求流动 在大鼠中进行细胞计数和RNA测序研究，特别关注MS和ALS模型，以揭示 CSF小胶质细胞的起源和功能。这一建议将奠定基础的定性， 能够调节CNS免疫的新细胞群。