Role of T cells in ischemic brain damage

T细胞在缺血性脑损伤中的作用

• 批准号: 9884832
• 负责人: Zsuzsanna Fabry
• 金额: $ 32.91万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884832
• 关键词: Acute; Acute Brain Injuries; Affect; Alteplase; Animal Model; Antibodies; Blocking Antibodies; Brain; Brain Injuries; Cause of Death; Cell physiology; Cells; Cerebral Ischemia; Chronic; Clinical Research; Data; Development; Fc Receptor; Flow Cytometry; Genetically Engineered Mouse; Goals; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Hypoxia; Immune response; Immune system; Immunohistochemistry; In Situ; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Ischemic Brain Injury; Ischemic Stroke; Lead; Manipulative Therapies; Maps; Mediator of activation protein; Middle Cerebral Artery Occlusion; Mus; Nervous System Trauma; Neuraxis; Neuronal Dysfunction; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phase; Production; Receptor Signaling; Regulatory Pathway; Reporter; Role; Signal Transduction; Stroke; T-Lymphocyte; TNF gene; Testing; Tissues; Transgenic Mice; Tumor-infiltrating immune cells; United States; Work; acute stroke; brain tissue; cell motility; cytokine; disability; in vivo; inflammatory milieu; interleukin-21; interleukin-21 receptor; ischemic injury; neuroinflammation; neuron loss; new therapeutic target; novel; post stroke; preclinical study; receptor; receptor expression; recruit; spatiotemporal; stroke model; stroke therapy; targeted treatment

PROJECT SUMMARY/ABSTRACT Stroke is one of the leading causes of death and disability worldwide and is the third leading cause of death and disability in the United States. Clinical and preclinical studies suggest the importance of inflammation in acute and chronic neuronal tissue damage following ischemic stroke; however, the mechanisms and cells involved in neuroinflammation are not fully understood. There is currently no available treatment for targeting the acute immune response that develops in the brain during cerebral ischemia, and no new treatment has been introduced to stroke therapy since the discovery of tissue plasminogen activator therapy in 1996. We discovered that interleukin 21 (IL21) is a major contributor to acute brain injury after ischemic stroke. IL21 expressing cells were detected in perivascular regions and the infarcted parenchyma of ischemic human brain tissues. This raises the possibility that IL21–targeting therapies adjunct to current treatments might be beneficial in stroke management. The long-term goal of this work is to understand how to manipulate the acute inflammation following ischemic injury in order to inhibit stroke-induced tissue damage. The objective of this proposal is to define the mechanisms by which pathogenic follicular helper T cells (Tfh) and IL21 are involved in acute stroke-induced injury. The specific hypothesis is that the recently discovered circulating pathogenic IL21-producing Tfh cells infiltrate into ischemic tissues in the brain, where IL21 contributes to tissue damage by inducing neuronal death. Three aims will study how Tfh cells and IL21 contribute to ischemic injury in the brain. In Aim 1, we will elucidate the pathways that drive IL21-producing Tfh cell infiltration, development and function in the CNS during different stages of ischemic injury induced by transient Middle Cerebral Artery Occlusion (tMCAO). We propose that selective Tfh cell recruitment blockers could decrease tissue damage in stroke. In Aim 2, we will evaluate spatiotemporal expression of IL21R in the ischemic brain and test potential regulator(s) of IL21R expression on neurons. We propose that inhibiting IL21R expression on neurons could decrease tissue damage in stroke. In Aim 3, we will characterize the role of IL21R on neurons in the pathogenesis of ischemic stroke. We will evaluate acute and chronic ischemic damage and the CNS inflammatory milieu in mice that selectively lack IL21R in neurons. Successful completion of this work will lead to a better understanding of the mechanism by which pathogenic IL21-producing cells promote damage in ischemic injury and identify new therapeutic targets in stroke.

项目摘要/摘要 中风是世界范围内导致死亡和残疾的主要原因之一，是第三大死亡原因 以及美国的残疾问题。临床和临床前研究表明炎症在脑出血中的重要性 缺血性卒中后急性和慢性神经元组织损伤；然而，机制和细胞 参与神经炎症的机制还不完全清楚。目前还没有可用的靶向治疗方法。 在脑缺血期间在大脑中发展的急性免疫反应，并且没有新的治疗方法 自1996年发现组织纤溶酶原激活剂疗法以来，已被引入中风治疗。我们 发现白介素21(IL21)是导致缺血性中风后急性脑损伤的主要因素。IL21 人脑缺血区血管周围和梗死灶内可见表达细胞 纸巾。这增加了一种可能性，即IL21靶向治疗是当前治疗的辅助手段 有益于中风的治疗。这项工作的长期目标是了解如何操纵 缺血性损伤后的急性炎症，以抑制中风引起的组织损伤。的目标是 本研究旨在明确致病卵泡辅助T细胞(TFH)和IL21的作用机制。 参与了急性中风引起的伤害。具体的假设是，最近发现的循环 致病的产生IL21的TFH细胞渗入脑内的缺血组织，在那里IL21对组织有贡献 通过诱导神经元死亡造成的损害。三个目标将研究TfH细胞和IL21在缺血性损伤中的作用 在大脑里。在目标1中，我们将阐明驱动IL21产生TFH细胞的渗透、发展的途径。 短暂性大脑中动脉缺血损伤不同阶段中枢神经系统功能的变化 闭塞(TMCAO)。我们认为选择性的TFH细胞募集阻滞剂可以减少组织损伤。 卒中。在目标2中，我们将评估IL21R在缺血脑中的时空表达并测试其潜能 神经元IL-21R表达调控因子S。我们认为抑制神经元上IL21R的表达可能 减少中风时的组织损伤。在目标3中，我们将表征IL21R在神经元中的作用。 缺血性中风的发病机制。我们将评估急性和慢性缺血性损伤和中枢神经系统 神经元中选择性缺乏IL21R的小鼠的炎症环境。 这项工作的成功完成将有助于更好地理解 致病的IL21产生细胞促进缺血性损伤的损伤并寻找新的治疗方法 中风中的目标。