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

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.

项目总结 Rett综合征是一种破坏性的神经发育障碍，给患者和他们的 家人。患者出现了健康的神经发育的初始阶段，紧随其后的是 在他们生命的头几年，严重的运动和认知衰退。患者通常患有步态 功能障碍、失语、癫痫发作和睡眠障碍。由于它主要是神经系统的表现， 这种由甲基CpG结合蛋白2(MeCP2)突变引起的X连锁疾病一直被研究得很多 作为一种神经元疾病。虽然MeCP2缺失会导致细胞内源性神经元功能障碍，但非神经性 机制也影响Rett综合征的进展，从而打开了旁路治疗的途径 对神经元的操纵。过去十年的研究揭示了神经免疫相互作用在 大脑的边界对大脑的健康发育和功能至关重要，这表明有可能 发现导致Rett综合征的新机制。神经免疫学领域的一项重大进展 脑膜淋巴网络的发现。脑膜淋巴管位于大脑的 外膜层，硬脑膜，在那里它们调节中枢神经系统(CNS)的液体容量和 脑脊液(CSF)持续清除出中枢神经系统。消融这些血管会损害脑脊液 清除，导致细胞外废物堆积和认知障碍。多发性硬化症的临床表现 RETT患者的癫痫发作、脑脊液容量增加以及脑脊液成分的炎性变化 脑脊液在正常情况下洗脑的脑脊液的灌流和清除方面的潜在损害。支持这一点 假设，我们的初步数据显示，脑脊液灌流贯穿整个大脑，以及一个主要的调节因素 正常的脑脊液动力学，即脑膜淋巴管，在MeCP2缺陷的Rett小鼠模型中大部分缺失 综合症。在这里，我们建议检验一种假设，即脑膜淋巴管的丢失，是由丢失引起的 脑膜巨噬细胞是Rett综合征的重要致病因素。我们的初步数据表明，这 脑膜淋巴覆盖率降低可能是脑膜巨噬细胞丢失的间接原因 通常为淋巴管提供营养支持。我们的数据还指向上游的，细胞固有的 骨髓造血或免疫细胞产生的损害是导致 观察到脑膜巨噬细胞丢失。第一个目标是使用最先进的转基因小鼠品系来 MeCP2缺失对颅骨骨髓造血和巨噬细胞影响的细胞类型特异性研究 差异化。第二个目标将使用先进的细胞替换策略和病毒过度表达工具 评估脑膜巨噬细胞和淋巴管的功能关系和治疗潜力。 患有雷特综合征。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，并确定新的和可获得的治疗目标，以帮助改善疾病。