Inflammatory mechanisms in cerebral ischemia

脑缺血的炎症机制

• 批准号: 10322430
• 负责人: Midori A Yenari
• 金额: $ 32.56万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 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/10322430
• 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

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

项目负责人/主要研究者（最后一名、第一名、中间名）： 项目总结/摘要 中风是一种重要的神经系统疾病，有效的治疗方法很少。理解机制 潜在的中风病理生理学可能有助于确定适当的治疗方法。后炎症 目前认为，中风至少在急性时可加重缺血性损伤，但在清除脑缺血性损伤中可能很重要。 坏死的碎片和启动再生过程。髓样细胞表达的触发受体- 2（TREM 2）是最近发现的参与先天免疫系统的受体。TREM 2结合至 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。TREM 2也是 在小胶质细胞上表达，促进吞噬作用。我们之前发现大脑中的TREM 2 常驻小胶质细胞在脑缺血后上调，其缺乏导致恶化的 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， 通过对骨髓嵌合小鼠的研究，脑小胶质细胞中的TREM 2似乎有助于 在循环骨髓细胞（单核细胞和巨噬细胞）中，其有益功能比TREM 2更多。 我们还观察到TREM 2在骨髓来源的基质细胞（BMSC）中上调， 移植在暴露于实验性中风的小鼠中。最近的研究在实验室和 临床试验集中在使用骨髓间充质干细胞改善中风的结果，但原因是， 治疗效果尚不完全清楚。我们实验室的初步观察表明， 从野生型小鼠收获并植入TREM 2缺陷型小鼠中改善了神经学结果 在实验性中风后，这与移植的脑组织中TREM 2的上调有关。 骨髓间充质干细胞我们还注意到，TREM 2缺乏导致M1增加（促炎，有害） 实验性中风后的极化与具有完整 TREM2.在目标1中，我们将确定BMSC治疗的机制是否是由于转化 或上调这些细胞成为TREM 2表达细胞，以及TREM 2阳性细胞的转移是否 骨髓细胞也可以改善神经学结果。在目标2中，我们将确定雌性小鼠是否 对这些干预措施作出类似的反应。目标3将探讨TREM 2如何参与 BMSC的有益作用，如果需要将小胶质细胞和巨噬细胞向M2分化， （抗炎，有益）表型。 OMB编号0925-0001/0002（2012年8月批准至2015年8月31日修订版）页码续页格式页码