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: 9319266
• 负责人: Huanyu Dou
• 金额: $ 44.69万
• 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 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319266
• 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; Drug Delivery Systems; Encephalitis; Future; Heart Arrest; Heart Diseases; Hospitals; Immune; Immune Targeting; Immune response; Immune system; Immunodeficient Mouse; Inbred BALB C Mice; 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; bone engineering; brain repair; clinical development; clinically relevant; cytokine; design; effective therapy; experience; human disease; immune activation; improved; in vivo; injury and repair; innovation; macrophage; neuron loss; novel; novel therapeutic intervention; novel therapeutics; prevent; public health relevance; repaired; response; success; transdifferentiation; treatment strategy

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该合作项目汇集了两个研究团队，他们在（1）由于心脏骤停和复苏引起的全脑缺血后再灌注损伤的治疗，（2） 通过全身免疫应答的神经元损伤和保护机制，和（3）向中枢神经系统（CNS）的全身药物递送。在寻找使用成人干细胞有效治疗全脑缺血的过程中，研究人员偶然发现了一种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的新机制。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对全脑缺血的炎症反应，并通过防止对神经胶质细胞的促炎损伤来保护选择性脆弱的神经元。该项目的主要目标是实现对全脑缺血的全身和脑免疫反应之间的耦合的机制理解，从而开发一种系统性治疗策略，以接近心脏骤停后的神经元修复。中心假设是，复苏后再灌注后期的大部分弥散性神经元丢失可以通过调整免疫系统关闭促炎反应并开启保护性免疫激活来预防和逆转。提出了一种创新的方法来劫持免疫细胞的天然修复潜力，并为以前未知的治疗领域塑造其细胞因子的功能性分泌。已经开发了小鼠心脏骤停和复苏的临床相关结果模型，以允许在良好控制的心脏骤停和复苏后的纵向存活研究中使用部分和完全免疫缺陷的转基因小鼠。该项目的具体目标 为：具体目标1：在免疫完全野生型小鼠中建立临床相关心脏骤停后对全脑缺血和再灌注损伤的全身和脑免疫应答之间的相关性;具体目标2：使用部分和完全免疫缺陷转基因小鼠来鉴定和区分神经元损伤和修复中来自促炎细胞因子和抗炎细胞因子的免疫贡献;具体目标3：设计骨髓源性巨噬细胞和树突状细胞，以恢复部分和完全免疫缺陷小鼠的靶向免疫应答，从而从机理上理解神经元损伤和保护中全身免疫应答的潜在过程;具体目标4：开发可能的体内治疗后策略，重点是在心脏骤停和复苏后野生型小鼠中使用RNA干扰技术重新平衡促炎和抗炎细胞因子。这些具体的研究将为最终确定治疗心脏骤停后全脑缺血的最有效策略铺平道路， 并将新的机械理解从台式连接到床边。

项目成果

Invasion of Peripheral Immune Cells into Brain Parenchyma after Cardiac Arrest and Resuscitation.

• DOI: 10.14336/ad.2017.0926
• 发表时间: 2018-06
• 期刊: Aging and disease
• 影响因子: 7.4
• 作者: Zhang C;Brandon NR;Koper K;Tang P;Xu Y;Dou H
• 通讯作者: Dou H

Fingerprint of Circulating Immunocytes as Biomarkers for the Prognosis of Brain Inflammation and Neuronal Injury after Cardiac Arrest.

• DOI: 10.1021/acschemneuro.3c00397
• 发表时间: 2023-12-06
• 期刊: ACS CHEMICAL NEUROSCIENCE
• 影响因子: 5
• 作者: Dou, Huanyu;Brandon, Nicole R.;Koper, Kerryann E.;Xu, Yan
• 通讯作者: Xu, Yan

Facile Gene Delivery Derived from Branched Low Molecular Weight Polyethylenimine by High Efficient Chemistry.

• DOI: 10.1166/jbn.2018.2620
• 发表时间: 2018-10-01
• 期刊: Journal of biomedical nanotechnology
• 影响因子: 2.9
• 作者: Zou L;Lee SY;Wu Q;Zhang H;Bastian A;Orji C;Payne G;Galvez A;Thomas T;Zhang Z;Dou H
• 通讯作者: Dou H