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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要脉络丛（CP）和脑脊液（CSF）系统在调节大脑方面发挥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分子的目录 CP-CSF 系统及其在大脑发育以及免疫-大脑相互作用中的作用。失调脑脊液的产生或循环会导致脑积水等疾病，并且已观察到脑脊液萎缩在多种中枢神经系统疾病中。这些在人类大脑疾病中的观察结果表明 CP-CSF 系统在脑部疾病的进展或恶化中发挥作用。人们对 CP 目标的兴趣日益浓厚脑脊液容量和神经炎症管理的治疗。事实上，最近，CP 的临床益处内镜下第三脑室造口术治疗中的凝血已在以下疾病的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- 由于脑脊液系统的局限性，脑脊液系统在神经科学中仍然是一个尚未充分探索的领域。许多可用工具来精确调节其功能。 NIH 资助机会 PA-21-219 “NINDS/NIMH 探索性神经科学研究联合资助 “计划”认识到对“有潜力带来突破的新工具或模型”的需求尚未得到满足神经科学界。”通过使用我们最近发现的新型转基因小鼠品系，我们的项目将通过 (1) 建立一种新工具来消除小鼠 CP 以及 (2) 建模来实现这些目标采用 CP 靶向治疗治疗脑积水。我们严格的初步数据表明（1）这条线只能在 CP 上皮细胞中诱导细胞凋亡，并且 (2) CP 消融导致心室容积部分至接近完全减少 50-90%，具体取决于药物的剂量和时间行政。我们将描述剂量效应的特征并调查积极和潜在的不利影响部分和近乎完全的 CP 消融对脑积水和其他健康大脑发育的影响。我们的综合 MRI、颅内压、基因表达、细胞因子分析和免疫组织化学表征将揭示这种新工具对颅内压、心室大小、CP 再生的影响能力和产后神经发育。这将拓宽我们对该函数的基本理解 CP 和 CSF 在围产期大脑发育中的作用。此外，我们基于需求的工具对于澄清问题也很重要 CP-CSF系统在脑积水的发病机制和治疗中的关键作用。该项目为阐明 CP-CSF 在大脑潜在发育中的作用提供了一个重要的平台和功能。通过建立一种新工具，可以在任何所需时间点（新生儿至小鼠）去除小鼠体内的 CP-CSF 成年期），我们的项目将为促进CP-CSF的研究做出重大贡献和影响神经科学和脑疾病等广泛主题的系统。