Injury Mechanisms and Systemic Immune Responses after Cerebral Global Ischemia

脑整体缺血后的损伤机制和全身免疫反应

• 批准号: 8631251
• 负责人: Huanyu Dou
• 金额: $ 46.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631251
• 关键词: Aftercare; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Attention; Blood Circulation; Bone Marrow; Brain; Brain Injuries; Brain Neoplasms; Cardiovascular Diseases; Cause of Death; Cell fusion; Cells; Central Nervous System Diseases; Cerebral Ischemia; Cerebrum; Country; Coupling; Crystallization; Cytokine Signaling; Cytoprotection; Data; Dendritic Cells; Dependence; Development; Drug Delivery Systems; Encephalitis; Engineering; Future; Heart Arrest; Heart Diseases; Hospitals; Immune; Immune response; Immune system; Immunodeficient Mouse; Induced Heart Arrest; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-10; Interleukin-4; Interleukin-6; Investigation; Ischemia; Leukocytes; Link; Microglia; Modeling; Mus; Neuraxis; Neuroglia; Neurological outcome; Neuronal Injury; Neurons; Outcome; Parkinson Disease; Pathway interactions; Patients; Phase; Process; RNA Interference; Rattus; Recovery; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Resuscitation; Shapes; Signal Transduction; Stem cells; Stroke; TNF gene; Technology; Testing; Therapeutic; Transgenic Mice; Trauma; Umbilical cord structure; Wild Type Mouse; active control; adult stem cell; brain repair; clinically relevant; cytokine; design; effective therapy; experience; human disease; immune activation; improved; in vivo; injury and repair; innovation; neuron loss; novel; novel therapeutic intervention; novel therapeutics; prevent; programs; public health relevance; repaired; response; signal processing; success; transdifferentiation; treatment strategy

Injury Mechanisms and Systemic Immune Responses after Cerebral Global Ischemia Summary This collaborative project brings together two investigative teams with over two decades of combined research experience in (1) the treatment of reperfusion injuries after global cerebral ischemia due to cardiac arrest and resuscitation, (2) mechanisms of neuronal injury and protection through systemic immune responses, and (3) systemic drug delivery to the central nervous system (CNS). In their search for effective treatment of global cerebral ischemia using adult stem cells, the investigators serendipitously discovered a novel mechanism of stem cell protection through cell signaling instead of transdifferentiation or stem-cell/host-cell fusion. Most importantly, the investigators found that this signaling process can strongly modulate the inflammation response to global ischemia and render protection to selectively vulnerable neurons by preventing pro- inflammatory damage to glial cells. The main objective of this project is to achieve a mechanistic understanding of the coupling between systemic and brain immune responses to global cerebral ischemia, thereby developing a systemic treatment strategy to approach neuronal repair after cardiac arrest. The central hypothesis is that most of the disseminated neuronal loss in the later phase of reperfusion after resuscitation can be prevented and reversed by tailoring the immune system to turn off pro-inflammatory responses and turn on protective immune activation. An innovative approach is proposed to hijack the immune cells' natural repairing potential and to shape their functional secretion of cytokines for a previously uncharted therapeutic territory. A clinically relevant outcome model of cardiac arrest and resuscitation in mice has been developed to allow the use of partially and completely immunodeficient transgenic mice in longitudinal survival studies after a well-controlled cardiac arrest and resuscitation. The specific aims of this project are: Specific Aim 1: To establish correlations between systemic and brain immune responses to global cerebral ischemia and reperfusion injuries after clinically relevant cardiac arrest in immunocomplete wild-type mice; Specific Aim 2: To use partially and completely immunodeficient transgenic mice to identify and differentiate immune contributions from pro- and anti-inflammatory cytokines in neuronal injury and repair; Specific Aim 3: To engineer bone-marrow-derived macrophagic and dendritic cells to restore the targeted immune response in partially and completely immunodeficient mice to achieve a mechanistic understanding of the underlying processes in systemic immune responses in neuronal injury and protection; and Specific Aim 4: To develop possible in vivo post-treatment strategies focusing on rebalancing the pro- and anti-inflammatory cytokines using RNA-interference technology in wild-type mice after cardiac arrest and resuscitation. These specific investigations will pave the way to ultimately identifying the most effective strategies to treat global ischemia after cardiac arrest, and to bridge new mechanistic understandings from benchtop to bedside.

全脑缺血损伤机制与系统免疫反应 总结 这个合作项目汇集了两个调查团队，他们拥有二十多年的综合研究经验。 在（1）由于心脏骤停引起的全脑缺血后再灌注损伤的治疗方面的经验， 复苏，（2）通过全身免疫反应的神经元损伤和保护机制，和（3） 全身性药物递送至中枢神经系统（CNS）。在寻求有效治疗全球性 利用成体干细胞进行脑缺血研究，研究人员偶然发现了一种新的机制， 通过细胞信号传导而不是转分化或干细胞/宿主细胞融合来保护干细胞。最 重要的是，研究人员发现，这种信号传导过程可以强烈调节炎症， 反应，并提供保护，以选择性脆弱的神经元，通过防止亲- 神经胶质细胞的炎症损伤。该项目的主要目标是实现一个机械化的 了解对全脑缺血的全身和脑免疫反应之间的耦合， 从而开发了一种系统性治疗策略以接近心脏骤停后的神经元修复。中央 假设大多数弥散性神经元损失是在复苏后再灌注的后期 可以通过调整免疫系统来阻止和逆转促炎反应， 保护性免疫激活提出了一种创新的方法来劫持免疫细胞的自然 修复潜力和塑造他们的功能分泌细胞因子的一个以前未知的治疗 领土已经开发了小鼠心脏骤停和复苏的临床相关结果模型 允许在纵向存活研究中使用部分和完全免疫缺陷的转基因小鼠 经过良好控制的心脏骤停和复苏。该项目的具体目标是： 具体目标1：建立对全脑免疫应答的全身和脑免疫应答之间的相关性 免疫完全野生型小鼠中临床相关心脏骤停后的缺血和再灌注损伤; 具体目的2：利用部分和完全免疫缺陷转基因小鼠进行鉴定和区分 促炎和抗炎细胞因子在神经元损伤和修复中的免疫作用; 具体目标3：工程化骨髓来源的巨噬细胞和树突状细胞，以恢复靶向的免疫应答。 部分和完全免疫缺陷小鼠的免疫应答，以实现对 神经元损伤和保护中全身免疫反应的潜在过程;以及 具体目标4：开发可能的体内治疗后策略，重点是重新平衡前和后治疗。 在心脏骤停后野生型小鼠中使用RNA干扰技术的抗炎细胞因子， 复苏术 这些具体的调查将为最终确定最有效的治疗策略铺平道路 心脏骤停后的全脑缺血，并将新的机制理解从台式到床边。