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：
10224352
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/10224352
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.

项目摘要/摘要体内大多数组织的自适应免疫涉及抗原或抗原呈递细胞的排水传统的淋巴管与将抗原呈现给T细胞的排水淋巴结。然而，中枢神经系统实质内没有常规淋巴管。另外，它已被假设抗原，抗原呈现细胞和CSF可能会从中枢神经系统排出淋巴管附近的淋巴管在稳态条件下，板或硬脑膜可维持液体稳态和抗原引流，但鲜为人知关于这些淋巴管在神经炎症中的作用。我们发现环形板附近的淋巴管经历了广泛的原位新淋巴管生成在实验性自身免疫性脑脊髓炎（EAE）期间，多发性硬化症的小鼠模型。我们的初步数据表明，这些新的淋巴管附近的丝布状板上的功能能够沥干CSF和曾经在CNS实质中的细胞。我们进一步发现在EAE期间，VEGFC蛋白是由在曲线板。这些数据是第一个描述在丝布状板附近的新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新形成的淋巴管靠近丝布状板，可自身免疫性和中枢神经系统中风。该提案的具体目标是（1）定义驱动的特征和调节机制丝布状板附近的新淋巴管发生（AIM 1）；（2）测试新淋巴管的功能在纤维状板附近，并将它们与不同的中枢神经系统区域淋巴管进行比较（AIM 2）；（3）了解在丝布状板附近加重或抑制新的淋巴管生成的翻译值，以便治疗中枢神经系统疾病（AIM 3）。 Neo-Lymphangiogensis的药理抑制或加剧以调节中枢神经系统疾病的病理可能具有CNS自身免疫性和缺血性创伤的潜在治疗值。