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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.

项目总结