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.

项目摘要 脑膜从CNS发育的最早阶段起就包裹着CNS，并作为保护性屏障持续存在。 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， 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 脑发育可能由脑膜缺陷引起。脑膜还含有独特的免疫和 血管细胞群（血液和血管），现在已知在神经免疫系统中起关键作用。 监测、脑脊液引流和CNS废物清除，从而支持整体CNS健康， 功能尽管如此，我们对细胞和分子机制的理解并不完整， 控制脑膜的形成。我们对不同的成纤维细胞的发育知之甚少 产生有助于控制大脑发育的因素，并可能在发展中发挥作用的人群。 其他脑膜细胞类型（免疫细胞）和邻近结构如颅骨。我们以前的工作 表明脑膜成纤维细胞群体的软脑膜，蛛网膜和硬脑膜层周围的前脑 在转录上是独特的，并且在脑发育的早期阶段开始表达层特异性标记。 我们和其他人先前已经表明转录因子Foxc1是脑膜层的关键 规范.在这里，我们建议使用一种新的脑膜条件Foxc1小鼠突变体与 单细胞转录组学（scRNAseq），开始确定：1）正常发育过程中， 脑膜成纤维细胞层群体，并确定信号转导通路的基础上失败的发展， Foxc1突变体和2）识别由产前脑膜成纤维细胞产生的控制 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赠款申请的基础试验数据，支持我们长期的研究， 长期的研究目标是研究脑膜控制中枢神经系统的发育和功能，将是一个重要的 资源研究人员研究脑膜相关的结构，过程，疾病或畸形。