Cellular mechanisms of perivascular fibroblast development and dependence on PDGF signaling

血管周围成纤维细胞发育的细胞机制和对 PDGF 信号传导的依赖

基本信息

批准号：
10578680
负责人：
Hannah Elizabeth Jones
金额：
$ 3.87万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578680
关键词：
3-Dimensional Address Adult Appearance Arteries Astrocytes Biochemical Biological Assay Blood Vessels Blood capillaries Brain Cell Line Cell physiology Cells Central Nervous System Cerebrospinal Fluid Cerebrovascular system Cicatrix Collagen Color Data Dependence Development Diameter Disease Ensure Fibroblasts Fluid Balance Future Goals Homeostasis Human Immune Immunologics Injury Investigation Knowledge Label Laboratories Ligands Liquid substance Maintenance Maps Meninges Metabolic Methods Modeling Molecular Mus Nervous System Physiology Neurodegenerative Disorders Nutrient Optical Methods Optics Oxygen Pathway interactions Pericytes Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Population Process Proliferating Reporter Rodent Role Signal Transduction Slice Smooth Muscle Myocytes Stroke Subarachnoid Space System Testing Tissues Tracer Training Transgenic Mice Vascular Smooth Muscle Vascular blood supply Veins Visualization Work arteriole brain health cell motility cell type central nervous system injury ex vivo imaging fluid flow glymphatic function glymphatic system improved in vivo inhibitor interest migration mouse development novel postnatal postnatal development receptor stem tool venule wasting

项目摘要

PROJECT SUMMARY Perivascular spaces (PVSs) are fluid-filled spaces surrounding vessels of the central nervous system, are thought to have important roles in maintenance of brain health, and are a unique niche for a variety of perivascular cell types. A cell type of particular interest is perivascular fibroblasts (PVFs) which are poorly characterized, and their functions are largely unknown. PVFs are known to reside on the outside the vascular smooth muscle layer of medium-to large-diameter vessels in the adult mouse central nervous system, and are primarily identified by expression of Collagen-1 and Platelet-derived growth factor receptor (PDGFR)a and PDGFRb. However, nearly nothing is known about the developmental origins, or the cellular and molecular mechanisms important for PVF development. Preliminary data suggests PVFs emerge from a population of cells in the meninges and gradually populate brain PVSs during postnatal development, but this has not yet been investigated further. These gap in knowledge is a major barrier to developing novel tools to investigate the role of PVFs in brain homeostasis and disease. The objective of this proposal is to investigate the developmental origins, cellular dynamics, and molecular signaling mechanisms involved in PVF development. In Aim 1, I will use a combination of transgenic mouse lines that label PVFs, optical tissue clearing, ex vivo imaging, and a multi-color lineage tracing reporter to investigate the cellular origins and dynamics of developing PVFs. In Aim 2, I will use intracisternal cerebrospinal fluid tracer assays to determine the relationship between the timing of PVF development and PVS function. Finally, in Aim 3 I will investigate PDGF signaling as a potential mechanism controlling PVF development. Together, this project will be the first to fully characterize how PVF development occurs and whether or not PDGF signaling is involved.

项目摘要血管周空间（PVSS）是中枢神经系统的血管周围充满液体的空间，人们认为在维持大脑健康方面具有重要的作用，并且是各种各样的独特利基市场血管周细胞类型。特别感兴趣的细胞类型是血管周成纤维细胞（PVF）表征，它们的功能在很大程度上是未知的。众所周知，PVF位于血管上成年小鼠中枢神经系统中中直径血管的平滑肌层，是主要通过表达胶原蛋白-1和血小板衍生的生长因子受体（PDGFR）A和 PDGFRB。但是，关于发育起源或细胞和分子几乎一无所知机制对于PVF开发很重要。初步数据表明PVFS来自细胞群在产后发育过程中脑膜和逐渐填充脑PVSS，但这还没有进一步调查。这些知识差距是开发新工具来研究角色的主要障碍大脑体内平衡和疾病中的PVF。该提议的目的是调查发展参与PVF发育的起源，细胞动力学和分子信号传导机制。在AIM 1中，我会使用标记PVF，光学组织清除，离体成像和A的转基因小鼠系的组合多色谱系追踪报告基因研究PVF的细胞起源和动力学。目标 2，我将使用肠内脑脊液示踪剂测定来确定 PVF开发和PVS功能。最后，在AIM 3中，我将研究PDGF信号作为潜在机制控制PVF开发。该项目一起将是第一个充分表征PVF开发方式的项目发生以及是否涉及PDGF信号。