Cell-Cell Interaction and Hypoxic Brain Injury

描述（由申请人提供）： 这是一个持续的计划项目，目前在10年，以确定缺氧缺血性脑损伤的细胞和分子机制。在以前的资助期间的研究集中在兴奋毒性神经元和神经元胶质细胞的相互作用。目前的建议扩大了这一范围，包括血管损伤和炎症的作用。越来越多的人认识到，减少缺血性脑损伤的方法还必须保护“神经血管单位”，包括血液、微血管内皮、星形胶质细胞和血脑屏障，以及周围的神经胶质实质。十名密切互动的教师调查人员将在三个研究项目中寻求新的方向。在项目1“缺血耐受和内皮保护”中，Jeff Gidday将使用脑内皮培养物和一种新的小鼠模型探索缺血耐受的微血管机制，在该模型中，重复低氧预处理促进持续数周的保护。中风和其他神经血管单位的疾病会影响大脑白色物质，在项目2“缺血性白色物质中轴突损伤的机制”中，Mark Goldberg将使用慢病毒载体指导分子抑制剂的表达，以确定轴突变性的下游途径。在项目3中，“CAA诱导的血管功能障碍的发病机制”，大卫霍尔茨曼和汉斯迪特里希将使用体内和原位方法来检查脑淀粉样血管病对小动脉功能的影响，这是老年人缺血性和出血性中风的一个新原因。这些项目将得到以下核心的支持：核心A：“管理和统计核心”，核心B：“动物模型”，核心C：“分子神经科学/病毒载体”，以及核心D：“显微镜检查”。“研究人员分享实验方法，包括体内和体外模型，先进显微镜的专业知识，以及在确定新的中风治疗方法方面的共同兴趣。 与公共卫生的相关性：每年约有70万美国人经历中风。本项目研究中风中脑损伤的机制。该项目的长期目标是确定潜在的新形式的治疗，以减少损伤和促进中风的恢复。

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. RELEVANCE FOR PUBLIC HEALTH: Approximately 700,000 Americans experience a stroke each year. This project examines mechanisms of brain injury in stroke. The long-term goal of this project is to identify potential new forms of therapy to reduce injury and promote recovery in stroke.