The vasculature of the central nervous system (CNS) is highly specialized and serves to restrict access of blood-borne factors to the CNS compartment. Several lines of evidence support the conclusion that the structural and functional attributes of this blood-brain barrier (BBB) are induced in endothelial cells (EC) by interaction with astrocytes. The objective of this section of the grant is to study the effect of EC/astrocyte interactions on cytokine and chemokine-induced inflammation in the CNS. Two experimental systems will be employed. The first will use a co-culture system of human umbilical vein endothelial (HUVE) cells and syngeneic astrocytes that we developed. In this system, it has been clearly demonstrated that astrocytes induce markers characteristic of BBB EC in HUVE. This model system permits us to specifically address the effect of astrocytes on inflammatory changes induced in HUVE by cytokines and chemokines. The second experimental system is a study of inflammation in the rabbit CNS using a combination of pathologic and electrophysiologic approaches. This system will permit us to compare and contrast the inflammatory effects of cytokines and chemokines in the retina and brain, and will address the question of regional specialization in the response of the CNS vasculature to these inflammatory agents. In the first specific aim, we will analyze the response to cytokines of EC and astrocytes in co-culture and cultured alone. The effect of EC/astrocyte co-culture on cytokine-induced adhesion molecule expression, chemokine expression and structural changes in the cell monolayers will be examined.
In specific aim 2, we will examine the functional correlates of chemokine and adhesion molecule expression in the co-culture model system. The role of adhesion molecule and chemokine expression on leukocyte migration across the EC/astrocyte monolayers will be investigated.
In specific aim 3, we will study mechanisms involved in cytokine-mediated regulation of these events. Suppressor cytokines will be tested for their ability to block cytokine and chemokine-mediated inflammation in vitro and in vivo. In specific 4, we will assess cytokine receptor expression by EC, astrocytes and these cells in co-culture and in tissues obtained from individuals with multiple sclerosis. Finally, in specific aim 5, we will examine cytokine-induced inflammation at different sites in the CNS. The long- term goal is to understand the response of the specialized vasculature of the CNS to inflammatory mediators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS011920-21
Application #
5215062
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
1996
Total Cost
Indirect Cost
Raine, Cedric S (2017) Multiple sclerosis: The resolving lesion revealed. J Neuroimmunol 304:2-6
Raine, Cedric S (2014) Autobiography series: a hitchhiker's road to neuropathology. J Neuropathol Exp Neurol 73:270-81
Brosnan, Celia F; Raine, Cedric S (2013) The astrocyte in multiple sclerosis revisited. Glia 61:453-65
D'Aversa, T G; Eugenin, E A; Lopez, L et al. (2013) Myelin basic protein induces inflammatory mediators from primary human endothelial cells and blood-brain barrier disruption: implications for the pathogenesis of multiple sclerosis. Neuropathol Appl Neurobiol 39:270-83
Lutz, Sarah E; Raine, Cedric S; Brosnan, Celia F (2012) Loss of astrocyte connexins 43 and 30 does not significantly alter susceptibility or severity of acute experimental autoimmune encephalomyelitis in mice. J Neuroimmunol 245:8-14
Safavi, Farinaz; Feliberti, Jason P; Raine, Cedric S et al. (2011) Role of ?? T cells in antibody production and recovery from SFV demyelinating disease. J Neuroimmunol 235:18-26
Gaupp, Stefanie; Arezzo, Joseph; Dutta, Dipankar J et al. (2011) On the occurrence of hypomyelination in a transgenic mouse model: a consequence of the myelin basic protein promoter? J Neuropathol Exp Neurol 70:1138-50
Lutz, Sarah E; Zhao, Yongmei; Gulinello, Maria et al. (2009) Deletion of astrocyte connexins 43 and 30 leads to a dysmyelinating phenotype and hippocampal CA1 vacuolation. J Neurosci 29:7743-52
Zhang, Yueting; Argaw, Azeb Tadesse; Gurfein, Blake T et al. (2009) Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proc Natl Acad Sci U S A 106:19162-7
Omari, Kakuri M; Lutz, Sarah E; Santambrogio, Laura et al. (2009) Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1. Am J Pathol 174:164-76

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