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Role of T cells in ischemic brain damage

T细胞在缺血性脑损伤中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘