Inflammatory mechanisms in cerebral ischemia

脑缺血的炎症机制

基本信息

批准号：
9893930
负责人：
Midori A Yenari
金额：
$ 33.53万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893930
关键词：
Acute Animals Anti-Inflammatory Agents Bacteria Behavioral Binding Bone Marrow Bone Marrow Transplantation Brain Brain Injuries Brain Ischemia Cell Therapy Cells Cerebral Ischemia Chimera organism Clinic Clinical Clinical Trials Data Distal Eukaryotic Cell Excision Exposure to Family Female Functional disorder Gender Granulocyte-Macrophage Colony-Stimulating Factor Harvest Hematopoietic stem cells Histologic IL4 gene Immune Immune response Impairment Implant In Vitro Inflammation Inflammatory Inflammatory Response Injury Innate Immune System Intervention Knock-in Laboratories LacZ Genes Microglia Middle Cerebral Artery Occlusion Modeling Mus Myeloid Cells Necrosis Nervous System Trauma Neurologic Neurological outcome Neurons Outcome Phagocytosis Phagocytosis Inhibition Phenotype Pilot Projects Principal Investigator Process Recovery Series Stroke Stromal Cells TREM2 gene Therapeutic Therapeutic Effect Tissues Transplantation Up-Regulation Wild Type Mouse Work angiogenesis brain cell brain tissue cell injury cell transformation cytokine effective therapy immunoreaction improved improved outcome in vivo interest ischemic injury macrophage male monocyte neurological recovery post stroke preclinical study programs receptor regenerative stroke outcome stroke patient stroke recovery synaptogenesis

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Project Summary/Abstract Stroke is a significant neurological illness with few effective treatments. Understanding mechanisms underlying stroke pathophysiology may help identify appropriate treatments. Inflammation following stroke is now recognized to potentiate ischemic injury at least acutely, but may be important in clearing necrotic debris and initiating regenerative processes. Triggering receptor expressed by myeloid cells- 2 (TREM2) is a recently discovered receptor involved in the innate immune system. TREM2 binds to anionic moieties found on bacteria and eukaryotic cells, as well as injured brain cells. TREM2 is also expressed on microglia, where it promotes phagocytosis. We previously found that TREM2 on brain resident microglia is upregulated following brain ischemia, and its deficiency leads to worsened outcome and near complete inhibition of phagocytosis of damaged brain tissue. Further, we discovered that, through the study of bone marrow chimeric mice, TREM2 in brain microglia seem to contribute more to its beneficial functions than TREM2 in circulating myeloid cells (monocytes and macrophages). We also observed that TREM2 is upregulated in bone marrow derived stromal cells (BMSCs) after transplantation in mice exposed to experimental stroke. Recent studies in both the laboratory and clinical trials have focused on the use of BMSCs to improve outcome from stroke, but reasons for this therapeutic effect are not fully clear. Preliminary observations in our lab showed that delivering BMSCs harvested from wildtype mice and implanted in TREM2 deficient mice improved neurological outcome following experimental stroke, and this was associated with upregulation of TREM2 in the transplanted BMSCs. We also noticed that TREM2 deficiency led to increased M1 (pro-inflammatory, detrimental) polarization after experimental stroke compared to inflammatory responses in wildtype mice with intact TREM2. In Aim 1, we will determine whether a mechanism of BMSC therapy is due to transformation or upregulation of these cells into TREM2 expressing cells, and whether the transfer of TREM2 positive myeloid cells may also improve neurological outcome. In Aim 2, we will determine whether female mice respond similarly to these interventions. Aim 3 will then explore how TREM2 may be involved in the beneficial effect of BMSCs and if it is required to polarize microglia and macrophages towards a M2 (anti-inflammatory, beneficial) phenotype. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

计划主任/首席研究员（最后，第一，中间）：项目摘要/摘要中风是一种重要的神经疾病，几乎没有有效的治疗方法。了解机制潜在的中风病理生理学可以帮助识别适当的治疗方法。炎症随后现在，中风被认为至少会急性减弱性损伤，但对于清除可能很重要坏死碎片和启动再生过程。触发由髓样细胞表达的受体 - 2（TREM2）是涉及先天免疫系统的最近发现的受体。 TREM2与在细菌和真核细胞以及受伤的脑细胞上发现的阴离子部分。 TREM2也是在小胶质细胞上表达，促进吞噬作用。我们以前发现trem2在大脑上脑缺血后，居民小胶质细胞上调，其缺乏导致恶化结果和几乎完全抑制受损脑组织的吞噬作用。此外，我们发现了通过研究骨髓嵌合小鼠，脑胶质细胞中的Trem2似乎有助于在循环髓样细胞（单核细胞和巨噬细胞）中，其比trem2的功能更重要。我们还观察到，在骨髓衍生的基质细胞（BMSC）中，TREM2在暴露于实验中风的小鼠中的移植。在实验室和临床试验的重点是使用BMSC来改善中风的结果，但原因是治疗作用尚不完全清楚。我们实验室中的初步观察表明，提供BMSC 从野生型小鼠收获并植入TREM2缺乏小鼠的神经系统结果实验性中风后，这与移植中的trem2上调有关 BMSC。我们还注意到Trem2缺乏导致M1增加（促炎，有害）实验中风后的极化与完整的野生型小鼠的炎症反应相比 trem2。在AIM 1中，我们将确定BMSC治疗的机制是否是由于转化引起的或将这些细胞上调为TREM2表达细胞，以及trem2阳性的转移是髓样细胞也可能改善神经系统结局。在AIM 2中，我们将确定雌性小鼠是否对这些干预措施的反应类似。 AIM 3然后将探讨如何参与trem2 BMSC的有益效应，如果需要使小胶质细胞和巨噬细胞偏振朝向M2 （抗炎，有益）表型。 OMB No. 0925-0001/0002（Rev. 08/12批准通过8/31/2015）页面延续格式页面