White matter damage is a central event in the pathophysiology of diverse CNS disorders, including stroke and vascular dementia. But most cerebrovascular studies still focus on gray matter. In our previous grant cycle, we developed the novel concept of the oligovascular niche, wherein cerebral endothelial cells support oligodendrocyte precursor cells (OPCs). However, near the end of our grant period, we discovered that this crosstalk may be bi-directional. OPCs can in turn support endothelial function including blood-brain barrier (BBB) integrity. Importantly, this bi-directional interactio between OPCs and cerebral endothelium does not stand in isolation. Our pilot data suggest that crosstalk between cerebral endothelium and OPCs may be modulated by other cells such as astrocytes. Therefore, this renewal grant will expand our oligovascular niche concept by testing the overall hypothesis that OPC-derived trophic factors regulate BBB function in white matter, and astrocytes are critical for regulating/modulating these bi-directional processes of oligovascular signaling. We will extend our pilot data and attempt to validate our hypothesis with three specific aims:
Aim 1 will define the mechanism for how OPCs support endothelial permeability in vitro and BBB in vivo, Aim 2 will assess the role of astrocytes in regulating OPC-endothelial interactions in vitro, and Aim 3 will validate the role of astrocytes for regulating OP-BBB interactions in vivo. These experiments should extend our original idea of the oligovascular niche into a more general gliovascular unit, wherein astrocytes regulate crosstalk between OPCs and endothelium. Dissecting cell-cell signaling pathways in this conceptual framework may lead us to new therapeutic treatments for white matter-related diseases in the CNS.

Public Health Relevance

Although white matter damage is a central event in the pathophysiology of diverse CNS disorders, most cerebrovascular studies still focus on gray matter. In our previous grant cycle, we developed the novel concept that trophic coupling between cerebral endothelial cells and oligodendrocyte precursor cells (OPCs) in the neurovascular niche is critical for white matter homeostasis. Our renewal study will extend our original idea of the oligovascular niche into a more general gliovascular unit, wherein astrocytes regulate the crosstalk between OPCs and endothelium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS065089-06
Application #
8885174
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Koenig, James I
Project Start
2009-04-01
Project End
2020-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Arai, Ken (2018) Stroke Literature Synopses: Basic Science (2018/May). Stroke 49:e270
Takase, Hajime; Liang, Anna C; Miyamoto, Nobukazu et al. (2018) Protective effects of a radical scavenger edaravone on oligodendrocyte precursor cells against oxidative stress. Neurosci Lett 668:120-125
Arai, Ken (2018) Stroke Literature Synopses: Basic Science. Stroke :
Maki, Takakuni; Choi, Yoon Kyung; Miyamoto, Nobukazu et al. (2018) A-Kinase Anchor Protein 12 Is Required for Oligodendrocyte Differentiation in Adult White Matter. Stem Cells 36:751-760
Arai, Ken (2018) Stroke Literature Synopses: Basic Science (2017/Dec). Stroke 49:e39-e40
Maki, Takakuni; Morancho, Anna; Martinez-San Segundo, Pablo et al. (2018) Endothelial Progenitor Cell Secretome and Oligovascular Repair in a Mouse Model of Prolonged Cerebral Hypoperfusion. Stroke 49:1003-1010
Arai, Ken (2017) Stroke Literature Synopses: Basic Science. Stroke 48:e193-e194
Arai, Ken (2017) Stroke Literature Synopses: Basic Science. Stroke 48:e85-e86
Arai, Ken (2017) Stroke Literature Synopses: Basic Science (2017/Aug). Stroke 48:e336-e337
Arai, Ken (2017) Stroke Literature Synopses: Basic Science. Stroke 48:e336-e337

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