Formation and Function of the Meninges

脑膜的形成和功能

• 批准号: 10578731
• 负责人: Julie Siegenthaler
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578731
• 关键词: Adult; Applications Grants; Arachnoid mater; Bioinformatics; Blood; Blood Vessels; Brain; Calvaria; Cell Separation; Cells; Central Nervous System; Cephalic; Cerebrospinal Fluid; Cerebrovascular system; Cerebrum; Complex; Congenital Abnormality; Congenital neurologic anomalies; Craniosynostosis; Data; Data Set; Defect; Development; Disease; Drainage procedure; Dura Mater; Endothelial Cells; Excision; FOXC1 gene; Failure; Fibroblast Growth Factor; Fibroblasts; Future; Gene Expression Profile; Genetic Transcription; Goals; Health system; Human; Immune; Impaired cognition; Impairment; Ligands; Lymphatic; Macrophage; Meningeal; Meninges; Molecular; Mus; Mutant Strains Mice; Mutation; Neurodevelopmental Disorder; Neuroimmune; Neurons; Osteoblasts; Pathway interactions; Patients; Phenotype; Population; Positioning Attribute; Process; Prosencephalon; RNA; Receptor Cell; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Stromal Cell-Derived Factor 1; Structure; Surgical sutures; Therapeutic; Time; Tissues; Tretinoin; Work; Writing; blood vessel development; bone; cell type; cerebral vein; cerebrovascular; experimental study; fetal; insight; lymphatic vessel; malformation; migration; mind control; motor impairment; mutant; nervous system development; neurogenesis; novel; prenatal; prevent; recruit; single-cell RNA sequencing; transcription factor; transcriptome; transcriptomics; wasting

Project summary The meninges encase the CNS from its earliest stages of development and persist as a protective covering for the adult CNS. Many studies show the meninges, in particular the meningeal fibroblasts, has vital roles in controlling developmental neurogenesis and neuronal migration and congenital defects in human brain development can arise from meningeal defects. The meninges also contain unique immune and vascular cell populations (blood and lymphatics) that are now known to serve key functions in neuro-immune surveillance, cerebrospinal fluid drainage and CNS waste removal, thus supporting overall CNS health and function. Despite this, we have an incomplete understanding of the cellular and molecular mechanisms that control formation of the meninges. We know very little about the development of the different fibroblast populations that produce factors that help control brain development and may have roles in development of other meninges cell types (immune cells) and adjacent structures like the calvarium. Our prior work demonstrates that meningeal fibroblast populations of the pia, arachnoid and dura layers around the forebrain are transcriptionally unique and begin to express layer specific markers at early stages of brain development. We and others have previously shown that the transcription factor Foxc1 is key for this meningeal layer specification. Here we propose to use a new, meninges conditional Foxc1 mouse mutant in combination with single cell transcriptomics (scRNAseq) to begin to identify: 1) the normal developmental progression of meningeal fibroblast layer populations and identify signaling pathways that underlie the failed development in Foxc1 mutants and 2) identify signals produced by prenatal meningeal fibroblasts that control maturation of other meningeal populations, in particular immune cells, and the adjacent calvarium. Completion of experiments outlined here will serve as foundational pilot data for future grant applications, support our long- term research goals in studying meninges control of CNS development and function and will be an important resource for researchers studying meninges-related structure, process, disease or malformation.

项目概要 脑膜从中枢神经系统发育的最早阶段就包裹着中枢神经系统，并持续发挥保护作用。 覆盖成人中枢神经系统。许多研究表明，脑膜，特别是脑膜成纤维细胞，具有至关重要的作用。 在控制人类发育神经发生和神经元迁移以及先天性缺陷中的作用 脑膜缺陷可能导致大脑发育。脑膜还含有独特的免疫和 目前已知血管细胞群（血液和淋巴管）在神经免疫中发挥关键功能 监测、脑脊液引流和中枢神经系统废物清除，从而支持中枢神经系统的整体健康和 功能。尽管如此，我们对细胞和分子机制的了解还不完全。 控制脑膜的形成。我们对不同成纤维细胞的发育知之甚少 产生有助于控制大脑发育并可能在发育中发挥作用的因子的人群 其他脑膜细胞类型（免疫细胞）和邻近结构（如颅骨）。我们之前的工作 表明前脑周围软脑膜、蛛网膜和硬脑膜层的脑膜成纤维细胞群 在转录上是独特的，并在大脑发育的早期阶段开始表达层特异性标记。 我们和其他人之前已经证明转录因子 Foxc1 是该脑膜层的关键 规格。在这里，我们建议使用一种新的脑膜条件性 Foxc1 小鼠突变体与 单细胞转录组学 (scRNAseq) 开始识别：1) 正常发育进程 脑膜成纤维细胞层群体并确定导致发育失败的信号通路 Foxc1 突变体和 2) 识别产前脑膜成纤维细胞产生的控制脑膜成纤维细胞成熟的信号 其他脑膜群，特别是免疫细胞，以及邻近的颅骨。完成 这里概述的实验将作为未来拨款申请的基础试点数据，支持我们的长期 长期研究目标是研究脑膜对中枢神经系统发育和功能的控制，并将成为一个重要的研究方向。 为研究脑膜相关结构、过程、疾病或畸形的研究人员提供的资源。