Ablating choroid plexus epithelial cells in the developing mouse brain: A new tool to approach CSF disorders

消融小鼠大脑发育中的脉络丛上皮细胞：治疗脑脊液疾病的新工具

• 批准号: 10605760
• 负责人: JUNE GOTO
• 金额: $ 45.69万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605760
• 关键词: Ablation; Address; Adult; Adverse effects; Affect; Alleles; Animal Model; Animals; Apoptosis; Apoptotic; Astrocytes; Atrophic; Biology; Blood; Blood Circulation; Brain; Brain Diseases; Catalogs; Cell Death; Central Nervous System Diseases; Cerebrospinal Fluid; Chickens; Child; Childhood; Choroid Plexus Epithelium; Clinical; Coagulation Process; Communities; Data; Defect; Developing Countries; Development; Diphtheria Toxin; Disease; Disease Progression; Dose; Epithelial Cells; Funding Opportunities; Future; Gene Expression; Genetic Models; Goals; Growth; Health; Histology; Human; Hydrocephalus; Immune; Impairment; Intervention; Intracranial Pressure; Joints; Knowledge; Magnetic Resonance Imaging; Maintenance; Microglia; Modeling; Molecular; Morphogenesis; Multiple Sclerosis; Mus; Mutant Strains Mice; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Natural regeneration; Neonatal; Neurosciences; Neurosciences Research; Outcome; Pathogenesis; Pathologic; Patients; Production; RNA; Regenerative capacity; Research; Research Project Grants; Research Proposals; Role; Sampling; Spinal Fluid Pressures; Structure of choroid plexus; System; Tamoxifen; Time; Transgenic Mice; United States National Institutes of Health; Ventricular; Ventriculostomy; adverse outcome; base; brain abnormalities; cytokine; design; developmental disease; diphtheria toxin receptor; in vivo; in vivo Model; innovation; interest; myelination; nano-string; neonatal brain; neonatal brain development; nervous system disorder; neurodevelopment; neurodevelopmental effect; neuroinflammation; novel; novel therapeutic intervention; perinatal brain; postnatal; pressure; programs; regenerative; relating to nervous system; response; synaptogenesis; targeted treatment; tool

Project Summary The choroid plexus (CP) and cerebral spinal fluid (CSF) system serve multiple active roles in regulating brain formation and the brain's overall health. Emerging new knowledge is determining catalogs of molecules in the CP-CSF system and their role in brain development as well as an immune-brain interaction. Dysregulation of CSF production or circulation causes diseases such as hydrocephalus, and CP atrophy has been observed in multiple CNS disorders. These observations in the human brain disorders indicate that the CP-CSF system has engaged roles in the brain disease progression or exacerbation. There is rising interest in CP-targeted therapies in CSF volume and neuroinflammation management. In fact, recently, clinical benefits of CP coagulation in endoscopic third ventriculostomy treatment have been demonstrated in the treatment of pediatric hydrocephalus patients in developing countries. However, contrary to its important roles, the CP- CSF system has mainly been remained an under-explored field in neuroscience due to limitations in the number of available tools to precisely modulate its functions. The NIH Funding Opportunity PA-21-219 " The Joint NINDS/NIMH Exploratory Neuroscience Research Grant program" recognizes the unmet need for "novel tools or models that have the potential to bring breakthroughs to the neuroscience community." By using a novel transgenic mouse line that we recently discovered, our project will address the goals by (1) establishing a new tool to ablate CP in mice and (2) modeling hydrocephalus brains with CP-targeted treatment. Our rigorous preliminary data indicated that (1) this line can induce exclusive apoptotic cell death only in the CP epithelial cells and (2) the CP ablation results in partial to near-complete 50-90% reduction in ventricular volume depending on the dose and timing of agent administration. We will characterize the dosing effects and investigate the positive and potential adverse effects of partial and near-complete CP ablation in hydrocephalus and otherwise healthy brain development. Our comprehensive MRI, intracranial pressure, gene expression, cytokine profiling, and immunohistochemical characterization will reveal the effects of this new tool on intracranial pressure, ventricle size, CP regeneration capacity, and postnatal neurodevelopment. This will broaden our fundamental understanding of the function of CP and CSF in perinatal brain development. In addition, our needs-based tools will be important in clarifying the key role of the CP-CSF system in the pathogenesis and treatment of hydrocephalus. This project provides an essential platform for elucidating the role of CP-CSF in underlying brain development and function. By establishing a new tool to remove CP-CSF in mice at any desired timepoints (neonatal to adulthood), our project will make significant contributions and impact on promoting studies of the CP-CSF system in a wide range of topics in neuroscience and brain diseases.

项目摘要 脉络丛（choroid plexus，CP）和脑脊液（cerebral spinal fluid，CSF）系统在脑的调节中起着多种积极的作用 形成和大脑的整体健康。不断出现的新知识正在确定分子的目录， CP-CSF系统及其在脑发育中的作用以及免疫-脑相互作用。失调 CSF的产生或循环导致疾病，如脑积水，并已观察到CP萎缩 多种中枢神经系统疾病这些在人脑疾病中的观察表明，CP-CSF系统 参与了脑部疾病的进展或恶化。对CP目标的兴趣越来越大 CSF容量和神经炎症管理的治疗。事实上，最近，CP的临床益处 内窥镜第三脑室内造口术治疗中的凝血已在治疗中得到证实 发展中国家的小儿脑积水患者。然而，与其重要作用相反，CP- CSF系统由于在神经科学中的局限性而主要仍然是一个未被探索的领域。 许多可用的工具来精确地调节其功能。 PA-21-219“NINDS/NIMH联合探索性神经科学研究资助” 该计划”认识到对“有可能带来突破的新工具或模型的未满足的需求” 对神经科学界来说。“通过使用我们最近发现的一种新的转基因小鼠品系， 该项目将通过（1）建立一种新的工具来消融小鼠CP和（2）建模来实现目标 脑积水脑与CP靶向治疗。我们严格的初步数据表明，（1）这条线 可以仅在CP上皮细胞中诱导排他的凋亡性细胞死亡，以及（2）CP消融导致 心室容积部分至接近完全减少50-90%，具体取决于药剂的剂量和时间 局我们将描述给药效应，并研究阳性和潜在不良反应。 部分和接近完全CP消融对脑积水和其他健康脑发育的影响。 我们的综合MRI、颅内压、基因表达、细胞因子谱和免疫组织化学 表征将揭示这种新工具对颅内压、脑室大小、CP再生的影响， 能力和产后神经发育。这将拓宽我们对功能的基本理解 CP和CSF在围产期脑发育中的作用此外，我们基于需求的工具在澄清 CP-CSF系统在脑积水发病机制和治疗中的关键作用。 该项目为阐明CP-CSF在潜在脑发育中的作用提供了一个重要平台 和功能通过建立一种新的工具来在任何期望的时间点（新生儿至 我们的项目将对促进CP-CSF的研究做出重大贡献和影响 系统在神经科学和脑疾病的广泛主题。