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.