The role of skull bone marrow-derived CNS macrophages in Rett syndrome.

颅骨骨髓源性中枢神经系统巨噬细胞在雷特综合征中的作用。

• 批准号: 10823514
• 负责人: Jose Alejandro Mazzitelli Perez
• 金额: $ 3.33万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-11-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10823514
• 关键词: Ablation; Arteries; Bathing; Biological Assay; Biology; Blood Vessels; Bone Marrow; Brain; Bypass; Cells; Central Nervous System; Cerebrospinal Fluid; Clinical; Data; Development; Disease; Drainage procedure; Dura Mater; Family; Functional disorder; Future; Gait; Hematopoiesis; Hematopoietic stem cells; Immune; Impaired cognition; Impairment; In Vitro; Inflammatory; Intercellular Fluid; Life; Link; Liquid substance; Lymphatic; Lymphatic function; Macrophage; Mediating; Meningeal; Meningeal lymphatic system; Meninges; Metabolic; Methyl-CpG-Binding Protein 2; Mus; Mutation; Myelogenous; Myeloid Cells; Myelopoiesis; Neurodevelopmental Disorder; Neuroimmune; Neurologic; Neuronal Dysfunction; Neurons; Organ; Pathogenesis; Patients; Penetration; Perfusion; Physiology; Production; Research; Rett Syndrome; Role; Seizures; Sleep disturbances; Specific qualifier value; Speech; System; Testing; Therapeutic; Tissues; Transgenic Mice; Treatment Efficacy; VEGFC gene; Vascular Endothelial Growth Factor C; Veins; Viral; Work; brain parenchyma; burden of illness; cell type; cerebrospinal fluid flow; cognitive regression; cranium; extracellular; glymphatic system; imaging modality; improved; in vivo; in vivo imaging; interstitial; lymphatic dysfunction; lymphatic vasculature; lymphatic vessel; monocyte; motor regression; mouse model; neuroimmunology; new therapeutic target; overexpression; progenitor; therapeutic evaluation; therapeutic target; tool; wasting; Ablation; Arteries; Bathing; Biological Assay; Biology; Blood Vessels; Bone Marrow; Brain; Bypass; Cells; Central Nervous System; Cerebrospinal Fluid; Clinical; Data; Development; Disease; Drainage procedure; Dura Mater; Family; Functional disorder; Future; Gait; Hematopoiesis; Hematopoietic stem cells; Immune; Impaired cognition; Impairment; In Vitro; Inflammatory; Intercellular Fluid; Life; Link; Liquid substance; Lymphatic; Lymphatic function; Macrophage; Mediating; Meningeal; Meningeal lymphatic system; Meninges; Metabolic; Methyl-CpG-Binding Protein 2; Mus; Mutation; Myelogenous; Myeloid Cells; Myelopoiesis; Neurodevelopmental Disorder; Neuroimmune; Neurologic; Neuronal Dysfunction; Neurons; Organ; Pathogenesis; Patients; Penetration; Perfusion; Physiology; Production; Research; Rett Syndrome; Role; Seizures; Sleep disturbances; Specific qualifier value; Speech; System; Testing; Therapeutic; Tissues; Transgenic Mice; Treatment Efficacy; VEGFC gene; Vascular Endothelial Growth Factor C; Veins; Viral; Work; brain parenchyma; burden of illness; cell type; cerebrospinal fluid flow; cognitive regression; cranium; extracellular; glymphatic system; imaging modality; improved; in vivo; in vivo imaging; interstitial; lymphatic dysfunction; lymphatic vasculature; lymphatic vessel; monocyte; motor regression; mouse model; neuroimmunology; new therapeutic target; overexpression; progenitor; therapeutic evaluation; therapeutic target; tool; wasting

PROJECT SUMMARY Rett syndrome is a devastating neurodevelopmental disorder with a significant burden on patients and their families. Patients present with an initial period of healthy neurological development, immediately followed by severe motor and cognitive regression during their first few years of life. Patients typically suffer from gait impairments, loss of speech, seizures, and sleep disturbances. Owing to its primarily neurological presentation, this X-linked disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2) has been mostly studied as a disease of neurons. While MeCP2 loss results in cell-intrinsic neuronal dysfunction, non-neuronal mechanisms also impact Rett syndrome progression, thus opening therapeutic avenues that bypass manipulation of neurons. Research over the past decade has shed light on neuroimmune interactions at the borders of the brain that are critical for healthy brain development and function, suggesting the possibility to uncover new mechanisms contributing to Rett syndrome. One major advance in the field of neuroimmunology has been the discovery of the meningeal lymphatic network. Meningeal lymphatic vessels reside in the brain’s outer membranous layer, the dura mater, where they regulate central nervous system (CNS) fluid volume and the continuous clearance of cerebrospinal fluid (CSF) out of the CNS. Ablation of these vessels impairs CSF clearance, resulting in extracellular waste accumulation and cognitive impairment. The clinical presentation of seizures, increased CSF volume, and inflammatory changes to the composition of CSF in Rett patients, suggests a potential impairment in the perfusion and clearance of the CSF that normally bathes the brain. Supporting this hypothesis, our preliminary data shows that CSF perfusion throughout the brain, as well as a major regulator of normal CSF dynamics, the meningeal lymphatics, is largely absent in an MeCP2-deficient mouse model of Rett syndrome. Here, we propose to test the hypothesis that the loss of meningeal lymphatics, resulting from a loss of meningeal macrophages, is an important contributor to Rett syndrome. Our preliminary data suggest that this decreased meningeal lymphatic coverage may result indirectly from the loss of meningeal macrophages, which typically provide trophic support to lymphatic vessels. Our data also points to an upstream, cell-intrinsic impairment in bone marrow hematopoiesis, or immune cell production, as the mechanism responsible for the observed loss in meningeal macrophages. The first aim will employ state-of-the-art transgenic mouse lines to study the cell type specific effects of MeCP2 loss on skull bone marrow hematopoiesis and macrophage differentiation. The second aim will employ advanced cell replacement strategies and viral overexpression tools to assess the functional relationship, as well as therapeutic potential, of meningeal macrophages and lymphatics in Rett syndrome. This work has the potential to both uncover new biology that is critical to Rett syndrome progression and identify new and accessible therapeutic targets to help ameliorate disease.

项目摘要 RETT综合征是一种毁灭性的神经发育障碍，对患者及其 家庭。患者出现了最初的健康神经系统发育，紧接着 在生命的头几年中，严重的运动和认知回归。患者通常患有步态 障碍，言语丧失，癫痫发作和睡眠障碍。由于其主要的神经系统表现， 这种由甲基-CPG结合蛋白2（MECP2）突变引起的X连锁疾病主要是研究 作为神经元疾病。 MECP2损失导致细胞内神经元功能障碍，而非神经元 机制还影响RETT综合征的进展，因此打开绕过的疗法途径 神经元的操纵。在过去的十年中，研究阐明了神经免疫相互作用 大脑边界对于健康的大脑发育和功能至关重要，这表明有可能 发现有助于RETT综合征的新机制。神经免疫学领域的一个重大进步 一直是脑膜淋巴网络的发现。脑膜淋巴管居住在大脑 外膜层，硬脑膜，它们调节中枢神经系统（CNS）流体体积和 CNS中脑脊液（CSF）的连续清除。这些容器的消融会损害CSF 清除，导致细胞外废物的积累和认知障碍。的临床表现 RETT患者中CSF​​组成的癫痫发作，CSF体积增加和炎症变化表明 通常会刺激大脑的CSF的灌注和清除率潜在的损害。支持这个 假设，我们的初步数据表明，整个大脑中的CSF灌注以及 在MECP2缺乏的RETT的MECP2缺乏的小鼠模型中，正常的CSF动力学，脑膜淋巴机在很大程度上不存在 综合征。在这里，我们建议检验以下假设：脑膜淋巴机的丧失是由于损失而引起的 脑膜巨噬细胞是RETT综合征的重要因素。我们的初步数据表明这一点 脑膜淋巴覆盖率下降可能是由于脑膜巨噬细胞的丧失而间接导致的，这 通常为淋巴视频提供营养支持。我们的数据还指向上游细胞中心 骨髓造血的损害或免疫细胞的产生，作为负责的机制 观察到脑膜巨噬细胞的损失。第一个目标将采用最先进的转基因鼠标线 研究MECP2损失对颅骨造血和巨噬细胞的细胞类型特异性影响 分化。第二个目标将采用先进的细胞更换策略和病毒过表达工具 评估脑膜巨噬细胞和淋巴管的功能关系以及治疗潜力 在Rett综合征中。这项工作有可能发现对Rett综合征至关重要的新生物学 进展并确定新的且易于获得的治疗靶标，以帮助改善疾病。