Modulating the post-stroke inflammatory response to improve outcome in models of cerebral ischemia

调节中风后炎症反应以改善脑缺血模型的结果

基本信息

批准号：
9920227
负责人：
Katrin I. Andreasson
金额：
$ 51.88万
依托单位：
STANFORD UNIVERSITY
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：
2018-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920227
关键词：
Ablation Adaptor Signaling Protein Alzheimer&apos s disease risk Amplifiers Anti-Inflammatory Agents Area B-Lymphocytes Brain Brain Injuries Cause of Death Cell Lineage Cells Cerebral Ischemia Colitis Data Dendritic Cells Dinoprostone Effectiveness Equilibrium Evolution Family member Gender Immune Immune response Immune signaling Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Innate Immune Response Intervention Intestines Ischemia Lead Ligands Membrane Microglia Modeling Mus Myelogenous Myeloid Cells PTGS2 gene Pathway interactions Patients Pattern recognition receptor Peptides Peripheral Phagocytes Pharmacology Phase Population Process Receptor Signaling Recovery Recovery of Function Regulation Research Rodent Model Sepsis Signal Pathway Signal Transduction Stroke Surface T-Lymphocyte TREM2 gene TYROBP gene Testing Therapeutic Thrombolytic Therapy Time Up-Regulation Validation Variant Work aged brain repair chemokine comorbidity conditional knockout disability functional outcomes genetic approach immune function improved improved outcome insight macrophage monocyte mouse model neuroprotection neurotoxic neutrophil novel therapeutic intervention post stroke protective effect receptor recruit response stroke outcome stroke recovery transcriptomics

项目摘要

Modulating the post-stroke inflammatory response to improve outcome in models of cerebral ischemia ABSTRACT inflammatory responses. Stroke is a multiphasic process, with an initial ischemic phase followed by secondary progression of injury from Following ischemia, microglia and macrophages accumulate in the ischemic area and produce inflammatory mediators and chemokines that initially recruit peripheral macrophages, neutrophils, dendritic cells, and later T and B cells. This post-stroke inflammatory response is both beneficial and injurious, as multiple and simultaneous immune pathways in distinct immune cell populations generate both beneficial and maladaptive immune responses. Because the time window of intervention of thrombolytic strategies is limited after onset of ischemia, and because attempts at neuroprotection after stroke have not shown positive results, the post-stroke inflammatory response represents an attractive target for intervention to reduce brain injury and accelerate functional recovery. The identification of specific immune pathways activated after stroke that could be modulated therefore represents an opportunity to improve and accelerate recovery after stroke. In previous studies, we have focused on the beneficial effects of inhibiting COX-2/PGE2 inflammatory signaling through the myeloid PGE2 EP2 receptor. In these studies, we identified Triggering Receptor Expressed on Myeloid cells-1, or TREM1, as highly regulated by inflammatory PGE2 EP2 signaling. TREM1 is an inflammatory membrane receptor that is expressed only on myeloid lineage cells and is unique in its function as an amplifier of maladaptive inflammatory responses. Our preliminary data suggest that this immune signaling cascade enhances innate immune responses after cerebral ischemia days after stroke. Using a combination of pharmacological and conditional knockout strategies to isolate the contribution of peripheral immune cells to stroke, we propose to identify the mechanisms of action of TREM1 signaling after stroke and test the hypothesis that inhibition of this pathway in the days after stroke will enhance brain repair and accelerate recovery.

调节中风后炎症反应以改善脑缺血模型的结果抽象的炎症反应。中风是一个多相过程，初始为缺血期，随后是继发性损伤的继发性进展缺血后，小胶质细胞和巨噬细胞在缺血区域积聚，产生炎症介质和趋化因子，最初招募外周巨噬细胞、中性粒细胞、树突状细胞，后来是 T 细胞和 B 细胞。这种中风后炎症反应既有益又有害，因为不同免疫细胞群中的多个且同时的免疫途径会产生有益的和适应不良的免疫反应。因为溶栓策略干预的时间窗是缺血发作后效果有限，并且因为中风后神经保护的尝试并未显示出积极的结果结果表明，中风后炎症反应是减少大脑损伤的干预措施的一个有吸引力的目标。损伤并加速功能恢复。中风后激活的特定免疫途径的鉴定因此，可以进行调节，这是改善和加速中风后恢复的机会。在之前的研究中，我们重点关注抑制 COX-2/PGE2 炎症信号传导的有益作用通过骨髓 PGE2 EP2 受体。在这些研究中，我们鉴定了表达于骨髓细胞 1 (TREM1) 受炎症 PGE2 EP2 信号传导高度调节。 TREM1 是一个仅在骨髓谱系细胞上表达且功能独特的炎症膜受体作为适应不良炎症反应的放大器。我们的初步数据表明，这种免疫信号级联增强中风后脑缺血后的先天免疫反应。使用结合药理学和条件敲除策略来分离外周细胞的贡献免疫细胞对中风的影响，我们建议确定中风后 TREM1 信号传导的作用机制检验以下假设：中风后几天抑制该通路将增强大脑修复加速恢复。