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Oligo-Vascular Signaling in Stroke

中风中的寡血管信号传导

基本信息

批准号：
9298742
负责人：
Ken Arai
金额：
$ 38.06万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9298742
关键词：
Adult Astrocytes Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Brain-Derived Neurotrophic Factor Cell physiology Cells Central Nervous System Diseases Cerebral Ischemia Cerebrum Coupling Data Disease Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Event Exhibits Filtration Financial compensation Functional disorder Grant Growth Factor Homeostasis In Vitro Ischemia Lead Maps Measures Mus Myelin Oligodendroglia Oligonucleotides Permeability Phosphorylation Process Proteins Rattus Recovery Role Signal Pathway Signal Transduction Source Stroke Supporting Cell Testing Tight Junctions Transforming Growth Factor alpha Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transgenic Mice Vascular Dementia Western Blotting brain endothelial cell cerebral hypoperfusion cerebrovascular experimental study fluorescein isothiocyanate dextran gray matter in vivo indexing inhibitor/antagonist intercellular communication mouse model neurovascular novel novel therapeutics oligodendrocyte precursor precursor cell protein expression public health relevance repaired response spatiotemporal white matter white matter damage white matter injury

项目摘要

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.

描述(由申请人提供)：白质损伤是包括中风和血管性痴呆在内的各种中枢神经系统疾病的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上。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前体细胞(OPC)。然而，在我们的授权期接近尾声时，我们发现这种串扰可能是双向的。OPC反过来可以支持内皮功能，包括血脑屏障(BBB)的完整性。重要的是，OPC和脑内皮细胞之间的这种双向相互作用并不是孤立的。我们的初步数据表明，脑内皮细胞和OPC之间的串扰可能受到其他细胞的调节，如星形胶质细胞。因此，这笔续期拨款将通过测试OPC来源的营养因子调节白质中的BBB功能，以及星形胶质细胞在调节/调节这些寡血管信号的双向过程中起关键作用的总体假设，扩展我们的少血管生态位概念。我们将扩展我们的试点数据，并尝试通过三个具体目标来验证我们的假设：目标1将定义OPC如何在体外支持内皮细胞通透性和体内BBB的机制，Aim 2将在体外评估星形胶质细胞在调节OPC-内皮相互作用中的作用，以及Aim 3将验证星形胶质细胞在体内调节OP-BBB相互作用的作用。这些实验应该将我们最初关于少血管利基的想法扩展到一个更一般的神经胶质血管单位，在那里星形胶质细胞调节OPC和内皮之间的串扰。在这个概念框架中解剖细胞-细胞信号通路可能会引导我们找到治疗中枢神经系统白质相关疾病的新方法。