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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

项目主管/首席研究员（后、一、中）：