Cell-Cell Interaction and Hypoxic Brain Injury

描述(由申请人提供)： 这是一个持续的项目，目前是第10年，以确定缺氧缺血性脑损伤的细胞和分子机制。在之前的资助时期，研究集中在兴奋性毒性神经元-神经元和神经元-神经胶质细胞的相互作用上。目前的提案将这一范围扩大到包括血管损伤和炎症的作用。人们越来越认识到，减少缺血性脑损伤的方法还必须保护由血液、微血管内皮细胞、星形胶质细胞和血脑屏障组成的“神经血管单位”以及周围的神经胶质实质。十名密切互动的学院研究人员将在三个研究项目中寻求新的方向。在项目1“缺血耐受性和内皮细胞保护”中，Jeff Gidday将利用脑内皮细胞培养和一种新的小鼠模型来探索缺血耐受性背后的微血管机制，在该模型中，重复低氧预适应促进持续数周的保护。中风和其他神经血管单位的紊乱会影响脑白质，在项目2“缺血性白质中轴突损伤的机制”中，Mark Goldberg将使用慢病毒载体来指导分子抑制物的表达，以确定轴突变性的下游路径。在项目3“CAA诱导的血管功能障碍的发病机制”中，David Holtzman和Hans Dietrich将使用活体和原位方法研究大脑淀粉样血管病变对小动脉功能的影响，小动脉功能是老年人缺血性和出血性中风的新兴原因。这些项目将得到以下核心的支持：核心A：“行政和统计核心”，核心B：“动物模型”，核心C：“分子神经科学/病毒载体”，核心D：“显微镜”。研究人员共享实验方法，包括体内和体外模型，先进显微镜方面的专业知识，以及在确定中风新治疗方法方面的共同兴趣。

DESCRIPTION (provided by applicant): This is a continuing Program Project, currently in year 10, to identify cellular and molecular mechanisms of hypoxic-ischemic brain injury. Research in the previous funding periods centered on excitotoxic neuron-neuron and neuron-glial interactions. The current proposal expands this scope to include the role of vascular injury and inflammation. There is growing recognition that approaches to reducing ischemic brain injury must also protect the "neurovascular unit," comprised of blood, microvascular endothelium, astrocytes, and blood-brain barrier, together with the surrounding neuroglial parenchyma. Ten closely interacting faculty investigators will pursue new directions in three research projects. In Project 1, "Ischemic tolerance and endothelial protection," Jeff Gidday will explore microvascular mechanisms underlying ischemic tolerance using cerebral endothelial cultures and a new mouse model in which repetitive hypoxic preconditioning promotes protection sustained over weeks. Stroke and other disorders of the neurovascular unit affect cerebral white matter, and in Project 2, "Mechanisms of axon injury in ischemic white matter," Mark Goldberg will use lentivirus vectors directing expression of molecular inhibitors to identify downstream pathways of axon degeneration. In Project 3, "Pathogenesis of CAA-induced vascular dysfunction," David Holtzman and Hans Dietrich will use in vivo and in situ approaches to examine effects of cerebral amyloid angiopathy on arteriolar function, an emerging cause of ischemic and hemorrhagic stroke in the elderly. These projects will be supported by the following Cores: Core A: "Administrative and statistical core", Core B: "Animal models", Core C: "Molecular neurosciences / viral vectors", and Core D: "Microscopy." The investigators share experimental approaches including in vivo and in vitro models, expertise in advanced microscopy, and a common interest in identifying new therapeutic approaches to stroke.