Physiologic and Pathologic Coupling in the Neurovascular Unit

神经血管单元的生理和病理耦合

• 批准号: 7637941
• 负责人: Eng H. Lo
• 金额: $ 124.07万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637941
• 关键词: Physiologic; Pathologic; Coupling; Neurovascular; Unit

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.

描述（由申请人提供）：神经血管单元的概念正在改变我们研究大脑功能和CNS疾病的方式。重点从纯神经元的焦点转移到了整合观点，其中所有脑细胞之间的细胞 - 细胞通信构成了功能和功能障碍的基础。这种新的PPG旨在剖析神经血管单元中生理和病理耦合的机制，重点是血管和神经元区室之间的相互作用。在项目1中，我们将评估脑内皮细胞和神经元之间的基质整联蛋白信号传导和营养耦合。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撑的丧失会导致神经元功能障碍和死亡。在项目2中，我们将检验以下假设：鞘氨酸-1-磷酸盐（S1P）充当一种自分泌和旁分泌介质，该介体刺激脑损伤后刺激神经元和血管增殖，从而将神经发生和血管生成偶联在一起。在项目3中，我们将研究强烈去极化神经元与神经胶质和血管之间发生的反向血管收缩性血液动力学偶联。正常大脑与缺血性大脑中血流动力耦合的差异应揭示出新的脑功能障碍途径。所有项目都将得到神经血管耦合核的支持，我们将在其中开发并应用新颖的光学成像技术，以在时空和时间上三个维度绘制神经血管脑功能。 Synergy内置在所有项目之间的紧密相互作用中。项目1中的整联蛋白信号如何影响项目2中的S1P，相反，S1P可以调节内皮BDNF的生产？项目1和2中定义的整合素，BDNF和S1P信号传导如何影响项目3中的反向血液动力学耦合？我们的核心提供的光学成像技术是否可以应用于项目1、2和3项目中的矩阵和营养耦合的体内模型？最后，管理核心将支持管理员和预算后勤，计算机数据库以及我们计划中所有部门的神经血管研讨会系列。这种高度整合的PPG应该使我们能够在许多级别上剖析神经血管耦合，包括在组织水平上快速血液动力学偶联，以及在细胞水平上缓慢的基质和慢速耦合。脑激活范例用于评估正常的生理耦合，并将疾病模型用作剖析病理偶联的“探针”。这些数据不仅会对脑功能的理解产生重大影响，还应让我们深入了解急性脑损伤和神经变性中功能失调的脑部功能失调。