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.

项目摘要 Rett综合征是一种破坏性的神经发育障碍，对患者及其家人造成重大负担。 家庭患者表现出健康的神经发育的初始期，随后立即出现 严重的运动和认知退化在他们生命的最初几年。患者通常患有步态 损伤、言语丧失、癫痫发作和睡眠障碍。由于其主要的神经表现， 这种由甲基-CpG结合蛋白2（MeCP 2）突变引起的X连锁疾病已经被研究得最多 神经元疾病虽然MeCP 2损失导致细胞内在神经元功能障碍，但非神经元功能障碍是由MeCP 2引起的。 机制也影响Rett综合征的进展，从而开辟了绕过 操纵神经元。过去十年的研究已经揭示了神经免疫相互作用， 大脑的边界对健康的大脑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个重大进展 是脑膜淋巴网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）的液体量， 持续清除CNS中的脑脊液（CSF）。消融这些血管会损害CSF 清除，导致细胞外废物积累和认知障碍。的临床表现 Rett患者的癫痫发作、CSF体积增加和CSF成分的炎性变化表明， 在灌注和清除CSF，通常沐浴大脑的潜在损害。支持这一 假设，我们的初步数据表明，整个大脑的CSF灌注，以及一个主要的调节因子， 在Rett的MeCP 2缺陷小鼠模型中， 综合征在这里，我们建议测试的假设，即损失的脑膜炎，造成损失的 脑膜巨噬细胞的增殖是雷特综合征的重要促成因素。我们的初步数据表明， 脑膜淋巴覆盖减少可能间接由脑膜巨噬细胞的损失引起， 通常为淋巴管提供营养支持。我们的数据还指出， 骨髓造血或免疫细胞产生的损害，作为导致 在脑膜巨噬细胞中观察到损失。第一个目标是使用最先进的转基因小鼠品系， 研究MeCP 2缺失对颅骨骨髓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替代策略和病毒过表达工具 评估脑膜巨噬细胞和巨噬细胞的功能关系以及治疗潜力 Rett综合征这项工作有可能揭示对雷特综合征至关重要的新生物学， 发展和确定新的和可获得的治疗靶点，以帮助改善疾病。