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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：
10449330
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449330
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 Fluid Balance Functional disorder Gene Expression Profile Glial Fibrillary Acidic Protein Heterogeneity ITGAX gene Immune Immunohistochemistry In Situ Inflammatory Ligands Liquid substance Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphedema 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 draining lymph node in vivo imaging inflammatory milieu lymph nodes lymphatic vessel macrophage monocyte mouse model nestin protein neuroinflammation podoplanin recruit targeted treatment testing access 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.

项目总结/文摘