Oligo-Vascular Signaling in Stroke

 描述（由申请方提供）：白色物质损伤是多种CNS疾病（包括卒中和血管性痴呆）病理生理学的中心事件。但大多数脑血管研究仍然集中在灰质。在我们之前的资助周期中，我们提出了少血管生态位的新概念，其中脑内皮细胞支持少突胶质细胞前体细胞（OPCs）。然而，在我们的授权期快结束时，我们发现这种串扰可能是双向的。OPC可以反过来支持内皮功能，包括血脑屏障（BBB）的完整性。重要的是，OPCs和脑内皮细胞之间的这种双向相互作用并不是孤立的。我们的试验数据表明，脑内皮细胞和OPCs之间的串扰可能是由其他细胞，如星形胶质细胞调制。因此，这项更新资助将通过测试OPC衍生的营养因子调节白色物质中的BBB功能的总体假设来扩展我们的寡血管生态位概念，星形胶质细胞对于调节/调节寡血管信号传导的这些双向过程至关重要。我们将扩展我们的试点数据，并试图验证我们的假设与三个具体的目标：目标1将定义的机制，OPCs如何支持内皮细胞的通透性在体外和血脑屏障在体内，目标2将评估星形胶质细胞的作用，在体外调节OPC内皮细胞的相互作用，和目标3将验证星形胶质细胞的作用，调节OP-BBB的相互作用在体内。这些实验应该扩展我们原来的想法寡血管龛到一个更一般的胶质血管单位，其中星形胶质细胞调节OPCs和内皮之间的串扰。在这个概念框架中剖析细胞-细胞信号通路可能会引导我们对中枢神经系统中与白色物质相关的疾病进行新的治疗。

 DESCRIPTION (provided by applicant): 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.