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）：白质损伤是多种中枢神经系统疾病（包括中风和血管性痴呆）病理生理学的核心事件，但大多数脑血管研究仍然集中在灰质上。然而，在我们的资助期即将结束时，我们发现这种串扰可能是双向的。转支持内皮功能，包括血脑屏障 (BBB) 完整性。重要的是，OPC 和脑内皮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，脑内皮和 OPC 之间的串扰可能受到其他因素的调节。因此，这项更新资助将通过测试 OPC 衍生的营养因子调节白质中的 BBB 功能以及星形胶质细胞对于调节/调节至关重要的总体假设来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验证我们的假设：目标 1 将定义 OPC 如何支持体外内皮通透性和体内 BBB 的机制，目标 2 将评估星形胶质细胞在体外调节 OPC-内皮相互作用的作用，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对少血管生态位的最初想法扩展到这一领域。星形胶质细胞调节 OPC 和内皮细胞之间的串扰，是一个更通用的胶质血管单元。在这个概念框架中剖析细胞间信号传导通路可能会为我们带来中枢神经系统白质相关疾病的新治疗方法。