Neuroinflammation-induced lymphangiogenesis in the CNS

中枢神经系统中神经炎症诱导的淋巴管生成

基本信息

批准号：
9769903
负责人：
Zsuzsanna Fabry
金额：
$ 37.61万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769903
关键词：
Alzheimer&apos s Disease Antibodies Antigen-Presenting Cells Antigens Area Astrocytes Autoimmunity Automobile Driving Biological Brain CD44 Antigens CNS autoimmunity Cells Central Nervous System Diseases Cervical lymph node group Characteristics Clinical Data Dendritic Cells Development Disease Drainage procedure Dura Mater Endothelial Cells Experimental Autoimmune Encephalomyelitis Flow Cytometry Functional disorder Genetic Transcription Glial Fibrillary Acidic Protein Heterogeneity Homeostasis ITGAX gene Immune Immunohistochemistry In Situ Inflammatory Ligands Liquid substance Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic vessel Lymphoid Lymphoid Cell Mediating Multiple Sclerosis Mus Myeloid Progenitor Cells Neurons Oligodendroglia Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Peripheral Pharmacology Proteins Receptor Protein-Tyrosine Kinases Regulation Regulatory Pathway Reporter Role Sculpture Source Spinal Cord Stroke T-Lymphocyte Testing Therapeutic Time Tissues Transgenic Mice Transgenic Organisms Trauma Tyrosine Kinase Inhibitor VEGFC gene Vascular Endothelial Growth Factor Receptor-3 Work adaptive immunity cribriform plate in vivo imaging inflammatory milieu lymph nodes macrophage monocyte mouse model nestin protein neuroinflammation podoplanin recruit targeted treatment transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Adaptive immunity in most tissues of the body involves the drainage of antigens or antigen presenting cells within conventional lymphatic vessels to the draining lymph nodes where antigen is presented to T cells. However, there are no conventional lymphatic vessels within the CNS parenchyma. Alternatively, it has been hypothesized that antigens, antigen presenting cells, and CSF may drain from the CNS into lymphatics near the cribriform plate or dura to maintain fluid homeostasis and antigen drainage during steady-state conditions, yet little is known about the role of these lymphatic vessels during neuroinflammation. We discovered that lymphatic vessels near the cribriform plate undergo extensive in situ neo-lymphangiogenesis during experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis. Our preliminary data show that these neo-lymphatic vessels near the cribriform plate are functionally able to drain both CSF and cells that were once in the CNS parenchyma. We further found the during EAE, VEGFC protein is produced by infiltrating macrophages and dendritic cells to promote VEGFR3 dependent neo-lymphangiogenesis near the cribriform plate. These data are the first to describe neo-lymphangiogenesis near the cribriform plate during neuroinflammation. The long-term objective of this project is to characterize the functionality and contribution of newly formed lymphoid vessels near to the cribriform plate to autoimmunity and stroke of the CNS. The specific objectives of this proposal are (1) to define the characteristics and regulatory mechanisms driving neo-lymphangiogenesis near the cribriform plate (Aim 1); (2) to test the functionality of neo-lymphatic vessels near the cribriform plate and compare them to different CNS area lymphatics (Aim 2); and (3) to understand the translational value of exacerbating or inhibiting neo-lymphangiogenesis near the cribriform plate in order to treat CNS diseases (Aim 3). Pharmacological inhibition or exacerbation of neo-lymphangiogensis to modulate pathology in CNS diseases may have potential therapeutic values for CNS autoimmunity and ischemic trauma.

项目概要/摘要身体大多数组织中的适应性免疫涉及抗原或抗原呈递细胞的排出传统淋巴管连接至引流淋巴结，抗原在此处呈递给 T 细胞。然而，中枢神经系统实质内没有传统的淋巴管。或者，有人假设抗原、抗原呈递细胞和脑脊液可能从中枢神经系统流入筛状附近的淋巴管板或硬脑膜在稳态条件下维持液体稳态和抗原引流，但知之甚少关于这些淋巴管在神经炎症过程中的作用。我们发现筛板附近的淋巴管经历广泛的原位新生淋巴管生成在实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症小鼠模型）期间。我们的初步数据显示，筛板附近的这些新淋巴管在功能上能够排出脑脊液和曾经存在于中枢神经系统实质中的细胞。我们进一步发现，在EAE过程中，VEGFC蛋白是由浸润巨噬细胞和树突状细胞促进 VEGFR3 依赖性新生淋巴管生成筛板。这些数据首次描述了筛板附近的新生淋巴管生成神经炎症。该项目的长期目标是表征功能和贡献筛板附近新形成的淋巴管对自身免疫和中枢神经系统中风的影响。该提案的具体目标是（1）明确驱动因素的特征和监管机制。筛板附近新生淋巴管生成（目标 1）； (2)检测新淋巴管的功能靠近筛板并将其与不同 CNS 区域淋巴管进行比较（目标 2）； (3) 理解加剧或抑制筛板附近新淋巴管生成的转化价值，以治疗中枢神经系统疾病（目标 3）。通过药理抑制或加剧新淋巴管生成来调节中枢神经系统疾病的病理学可能对中枢神经系统自身免疫和缺血性创伤具有潜在的治疗价值。