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(CP)和脑脊液(CSF)系统在脑调节中起着多种积极作用 形成和大脑的整体健康。新兴的新知识正在确定宇宙中的分子目录 CP-CSF系统及其在脑发育和免疫-脑相互作用中的作用。失调症 脑脊液的产生或循环会引起疾病，如脑积水，并观察到脑脊液萎缩 在多种中枢神经系统疾病中。这些在人脑疾病中的观察表明，CP-CSF系统 在脑部疾病的进展或恶化中扮演了角色。人们对CP目标的兴趣与日俱增 脑脊液容量和神经炎症管理的治疗。事实上，最近，CP的临床益处 内窥镜下第三脑室造瘘术中的凝固性治疗已被证实用于治疗 发展中国家的儿童脑积水患者。然而，与其重要作用相反，CP- 由于脑脊液系统的局限性，脑脊液系统一直是神经科学中一个未被充分开发的领域。 可用于精确调整其功能的工具的数量。 美国国立卫生研究院资助机会PA-21-219“NINDS/NIMH联合探索性神经科学研究补助金 对有可能带来突破的新工具或模式，该计划“认识到未得到满足的需求” 通过使用我们最近发现的一种新型转基因小鼠品系，我们的 该项目将通过(1)建立一种新的工具来消融小鼠的CP和(2)建模来解决这些目标 脑积水的CP靶向治疗。我们严谨的初步数据表明：(1)这条线路 仅在CP上皮细胞中诱导排他性的凋亡细胞死亡和(2)CP消融导致 根据药物剂量和时间的不同，部分到接近完全的脑室容量减少50%-90% 行政管理。我们将描述剂量效应，并调查其积极和潜在的不良反应。 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。 我们的综合核磁共振成像、颅内压、基因表达、细胞因子分析和免疫组织化学 特征将揭示这一新工具对颅内压、脑室大小、脑膜再生的影响 能力和后天神经发育。这将扩大我们对功能的基本理解 脑脊液和脑脊液在围产期脑发育中的作用此外，我们基于需求的工具将在澄清 脑脊液系统在脑积水发病和治疗中的关键作用 该项目为阐明CP-CSF在脑发育中的作用提供了一个重要的平台 和功能。通过建立一种新的工具来在任何所需的时间点(新生儿到小鼠)清除小鼠的CP-CSF 成年)，我们的项目将对促进CP-CSF的研究做出重大贡献和影响 系统涉及神经科学和脑部疾病的广泛主题。