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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：
10384535
负责人：
Hannah Elizabeth Jones
金额：
$ 3.78万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
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/10384535
关键词：
3-Dimensional Address Adult Appearance Arteries Astrocytes Biochemical Biological Assay Blood Vessels Blood capillaries Brain Caliber Cell Line Cell physiology Cells Cerebrospinal Fluid Cerebrovascular system Cicatrix Collagen Color Data Dependence Development 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 Neuraxis Neurodegenerative Disorders Nutrient Optical Methods Optics Oxygen Pathway interactions Pericytes Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor alpha Receptor Population Process 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 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.

项目总结血管周围间隙(PVS)是围绕中枢神经系统血管的充满液体的间隙，被认为在维持大脑健康方面起着重要作用，是各种血管周围细胞类型。一种特别令人感兴趣的细胞类型是血管周围成纤维细胞(PVF)，这种细胞很差它们的特性，它们的功能在很大程度上是未知的。已知PVF位于血管的外部成年小鼠中枢神经系统中中到大直径血管的平滑肌层，并主要通过胶原-1和血小板衍生生长因子受体(PDGFR)a和 PDGFRb.然而，关于发育起源或细胞和分子方面的知识几乎一无所知。对PVF发展很重要的机制。初步数据表明，PVF来自于一群细胞在出生后发育过程中，脑膜和逐渐填充的脑室管瘤，但这还没有进一步调查。这些知识上的差距是开发新工具来研究这一角色的主要障碍 PVF在大脑动态平衡和疾病中的作用。这项建议的目的是调查发展的 PVF发生的起源、细胞动力学和分子信号机制。在《目标1》中，我将使用标记PVF的转基因小鼠系的组合、光学组织清除、体外成像和多色谱系追踪记者，调查发育中的PVF的细胞起源和动力学。在AIM 2、我会用脑池内脑脊液示踪分析来确定时间的关系 PVF开发和PVS功能。最后，在目标3中，我将研究PDGF信号作为一种潜在的机制控制PVF的发展。总之，这个项目将是第一个全面描述PVF开发方式的项目是否发生以及是否涉及PDGF信令。