Local Skull Marrow Sensing and Response to CNS Inflammation

局部颅骨对中枢神经系统炎症的感知和反应

• 批准号: 10654045
• 负责人: Charles P. Lin
• 金额: $ 68.08万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654045
• 关键词: Acceleration; Acute; Anatomy; Antigens; Area; Bacteria; Bacterial Meningitis; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Vessels; Bone Marrow; Bone Marrow Cells; Brain; Bypass; Cells; Central Nervous System; Central Nervous System Diseases; Cephalic; Cerebrospinal Fluid; Cervical lymph node group; Circulation; Clinical; Custom; Data; Drainage procedure; Emergency Situation; Environment; Event; Head; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Image; Immune; Immunology; Infection; Inflammation; Inflammatory; Intercellular Fluid; Intravenous; Knowledge; Label; Leukocytes; Lymphatic; Marrow; Meningeal; Meningeal lymphatic system; Meninges; Meningitis; Molecular; Mus; Neurologic; Neurosciences; Phenotype; Route; Sampling; Shapes; Signal Transduction; Site; Streptococcus pneumoniae; Structure of choroid plexus; Surveys; System; Testing; Time; Toll-like receptors; Tracer; Veins; Venous; Ventricular; Work; arachnoid villi; bioluminescence imaging; brain health; brain magnetic resonance imaging; cisterna magna; cortical bone; cranium; density; image guided; intravital imaging; intravital microscopy; irradiation; long bone; lymphatic vessel; migration; millimeter; neurological recovery; non-invasive imaging; novel; programs; response; single cell sequencing; single-cell RNA sequencing; tool; wasting

Cerebrospinal fluid (CSF) drains into venous blood and into meningeal lymphatic vessels. In this application, we will test the overarching hypothesis that there exists a third CSF exit route via skull channels into the cranial bone marrow. Three years ago, we described the existence of sub-millimeter channels connecting skull marrow cavities with the dural vasculature in mice and humans, and that leukocytes produced in the cranial bone marrow migrate towards the inflamed central nervous system (CNS) through these channels. Investigating the skull channels further, we recently made the surprising observation of CNS — skull marrow crosstalk in the opposite direction: fluorescent CSF tracers injected into the cisterna magna migrate through skull channels in a perivascular fashion and accumulate in specific skull marrow areas distinct from regions labeled by intravenous blood pool markers. We here propose to systematically study CSF egress through skull channels in the steady state and in bacterial meningitis, testing the hypothesis that the skull bone marrow is a privileged site of hematopoiesis that constantly surveys brain health via sampling the CSF for danger signals. We will begin with a rigorous assessment of CSF skull channel outflow in healthy mice, establishing its route, size constraints, and the marrow microenvironment receiving CSF. Motivated by our preliminary data showing bacterial migration through skull channels into the cranial bone marrow, we will then test the relevance of CSF skull egress in mice with bacterial meningitis induced by Streptococcus pneumoniae, clinically the most prevalent strain. The work in mice with meningitis will reveal how skull channel CSF drainage changes in inflammatory CNS conditions. This Co-PI application unites three different labs, creating a unique set of complimentary expertise in neuroscience, intravital imaging, immunology and hematology. We propose to leverage custom-developed tools such as advanced imaging of the hematopoietic niche, image-guided single cell sequencing, non-invasive imaging for phenotyping of infection and inflammation, in combination with the fields' gold standard assays. The program is based on bold preliminary data, will clarify the importance of previously unknown CSF signaling to the skull marrow, and potentially advance knowledge in a setting of clear clinical need, bacterial meningitis.

脑脊液（CSF）流入静脉血和脑膜淋巴管。在本申请中， 我们将检验总体假设，即存在第三条脑脊液出口途径，通过颅骨通道进入颅骨 骨髓三年前，我们描述了亚毫米通道的存在， 在小鼠和人类中，骨髓腔与硬脑膜血管系统，以及在颅骨中产生的白细胞 骨髓通过这些通道向发炎的中枢神经系统（CNS）迁移。 为了进一步研究颅骨通道，我们最近对中枢神经系统-颅骨骨髓进行了令人惊讶的观察。 相反方向的串扰：注入小脑延髓池的荧光CSF示踪剂通过 以血管周围的方式形成颅骨通道，并在特定的颅骨骨髓区域积聚， 由静脉血池标记物标记。我们在这里建议系统地研究脑脊液通过颅骨的流出 通道在稳定状态和细菌性脑膜炎，测试的假设，头骨骨髓是一个 造血的特权网站，不断调查大脑健康通过采样脑脊液的危险信号。 我们将开始对健康小鼠的CSF颅骨通道流出进行严格评估，确定其途径， 尺寸限制和接受CSF的骨髓微环境。我们的初步数据显示 细菌通过颅骨通道迁移到颅骨骨髓，然后我们将测试CSF的相关性。 在肺炎链球菌引起的细菌性脑膜炎小鼠中，临床上最常见的 流行菌株在患有脑膜炎的小鼠中的工作将揭示颅骨通道CSF引流如何变化， 炎症性CNS病症。此Co-PI应用程序将三个不同的实验室结合在一起， 在神经科学、活体成像、免疫学和血液学方面的专业知识。我们建议 利用定制开发的工具，如造血生态位的高级成像，图像引导的单 细胞测序，用于感染和炎症表型分型的非侵入性成像，与 菲尔兹的金标准分析。该计划是根据大胆的初步数据，将阐明的重要性， 以前未知的CSF信号传导到颅骨骨髓，并可能在明确的环境中提高知识。 临床需要，细菌性脑膜炎。