Physiologic and Pathologic Coupling in the Neurovascular Unit

描述(申请人提供)：神经血管单位的概念正在改变我们研究大脑功能和中枢神经系统障碍的方式。重点从单纯的神经元关注转向一种综合的观点，在这种观点中，所有脑细胞之间的细胞-细胞交流形成了功能和功能障碍的基础。这一新的PPG试图剖析神经血管单位中生理和病理耦合的机制，重点放在血管和神经元之间的相互作用上。在项目1中，我们将评估基质整合素信号和脑内皮细胞与神经元之间的营养偶联。我们假设内皮是脑源性神经营养因子(BDNF)的重要来源，因此内皮基质完整性和血管营养支持的丧失会导致神经元功能障碍和死亡。在项目2中，我们将测试假设，即1-磷酸鞘氨醇(S1P)作为自分泌和旁分泌介质，刺激脑损伤后神经元和血管的增殖，从而将神经发生和血管生成耦合在一起。在项目3中，我们将研究强烈去极化的神经元、神经胶质细胞和血管之间发生的反向血管收缩血流动力学耦合。正常和缺血脑血流动力学耦合的差异应该揭示脑功能障碍的新途径。所有项目都将得到神经血管耦合核心的支持，我们将在那里开发和应用新的光学成像技术，在空间和时间上绘制三维的神经血管大脑功能图。协同作用内置于所有项目之间的密切互动中。项目1中的整合素信号如何影响项目2中的S1P，反过来，S1P能否调节内皮细胞BDNF的产生？项目1和2中定义的整合素、BDNF和S1P信号如何影响项目3中测量的反向血流动力学耦合？我们的核心提供的光学成像技术能否应用于项目1、2和3中破坏的基质和营养耦合的活体模型？最后，行政核心将支持行政和预算后勤，一个计算机数据库，以及我们计划中代表的所有部门的神经血管研讨会系列。这种高度整合的PPG应该使我们能够在多个水平上解剖神经血管耦合，包括组织水平上的快速血流动力学耦合，以及细胞水平上的慢速基质和营养耦合。脑激活范式被用来评估正常的生理耦合，而疾病模型被用来作为“探针”来剖析病理耦合。这些数据不仅将对了解大脑功能产生重大影响，还应该让我们深入了解急性脑损伤和神经退行性变时功能障碍的大脑是如何恶化的。

DESCRIPTION (provided by applicant): The concept of the neurovascular unit is changing the way we investigate brain function and CNS disorders. The emphasis shifts from a purely neuronal focus towards an integrative view where cell-cell communication between all brain cells forms the basis for function and dysfunction. This new PPG seeks to dissect mechanisms of physiologic and pathologic coupling in the neurovascular unit, with a focus on interactions between vascular and neuronal compartments. In Project 1, we will assess matrix integrin signaling and trophic coupling between cerebral endothelial cells and neurons. We hypothesize that endothelium is a significant source of brain-derived neurotrophic factor (BDNF), so that loss of endothelial matrix integrity and vascular trophic support leads to neuronal dysfunction and death. In Project 2, we will test the hypothesis that sphingosine-1-phosphate (S1P) acts as an autocrine and paracrine mediator that stimulates both neuronal and vascular proliferation after brain injury, thus coupling together neurogenesis and angiogenesis. In Project 3, we will study the reverse vasoconstrictive hemodynamic coupling that occurs between intensely depolarized neurons and glia and the blood vessel. Differences in hemodynamic coupling in normal versus ischemic brain should reveal new pathways of brain dysfunction. All projects will be supported by a Neurovascular Coupling Core, where we will develop and apply novel optical imaging techniques to map neurovascular brain function in three dimensions over space and time. Synergy is built into close interactions between all projects. How do integrin signals in Project 1 affect S1P in Project 2, and conversely, can S1P modulate endothelial BDNF production? How does integrin, BDNF and S1P signaling defined in Projects 1 and 2 affect the reverse hemodynamic coupling measured in Projects 3? And can the optical imaging techniques provided by our Core be applied to the in vivo models of disrupted matrix and trophic coupling in Projects 1, 2 and 3? Finally, an Administrative Core will support admin and budget logistics, a computer database, and a neurovascular seminar series across all the departments represented in our program. This highly integrated PPG should enable us to dissect neurovascular coupling at many levels, including fast hemodynamic coupling at the tissue level, as well as slow matrix and trophic coupling at the cellular level. Brain activation paradigms are used to assess normal physiologic coupling, and disease models are used as "probes" to dissect pathologic coupling. These data will have significant impact not only on the understanding of brain function, but should also give us insight into how dysfunctional brain deteriorates in acute brain injury and neurodegeneration.