Formation and Function of the Meninges

脑膜的形成和功能

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要这些脑膜从最早的发展阶段包围了中枢神经系统，并一直持续为保护成人中枢神经系统的覆盖。许多研究表明脑膜，特别是脑膜成纤维细胞，至关重要人类控制发育神经发生和神经元迁移和先天性缺陷中的作用脑膜缺陷可能引起大脑发育。脑膜还包含独特的免疫和现在已知可以在神经免疫中发挥关键功能的血管细胞种群（血液和淋巴管）监视，脑脊液排水和CNS废物清除，从而支持总体CNS健康和功能。尽管如此，我们对细胞和分子机制仍有不完全理解脑膜的控制形成。我们对不同成纤维细胞的发展知之甚少产生有助于控制大脑发育的因素的人群，并可能在发展中发挥作用其他脑膜细胞类型（免疫细胞）和相邻的结构（如钙）。我们先前的工作证明PIA，蛛网膜和硬脑膜层的脑膜成纤维细胞周围围绕前脑在转录上是独特的，并在大脑发育的早期开始表达特定标记。我们和其他人以前已经表明，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，有条件的Foxc1小鼠突变体单细胞转录组学（SCRNASEQ）开始识别：1）在 FOXC1突变体和2）确定由控制成熟的产前脑膜成纤维细胞产生的信号其他脑膜群体，尤其是免疫细胞和相邻的钙。完成这里概述的实验将作为未来赠款应用程序的基础试验数据，支持我们的长期在研究CNS开发和功能的脑膜控制方面的术语研究目标将是重要的研究与脑膜相关的结构，过程，疾病或畸形的研究人员的资源。