Inflammatory mechanisms in cerebral ischemia

项目总监/首席调查员(最后、第一、中间)： 项目摘要/摘要 中风是一种严重的神经系统疾病，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能有助于确定适当的治疗方法。炎症随之而来 中风现在被认为至少在急性加重缺血性损伤，但在清除方面可能是重要的。 坏死性碎屑和启动再生过程。触发髓系细胞表达的受体- 2(TREM2)是最近发现的一种参与先天免疫系统的受体。TREM2绑定到 在细菌和真核细胞以及受损脑细胞中发现的阴离子部分。TREM2也是 表达在小胶质细胞上，促进吞噬作用。我们之前发现TREM2对大脑有影响 脑缺血后驻留的小胶质细胞上调，其缺失导致病情恶化 结果和几乎完全抑制受损脑组织的吞噬功能。更进一步，我们发现 通过对骨髓嵌合小鼠的研究，大脑小胶质细胞中的TREM2似乎起到了作用 在循环中的髓系细胞(单核细胞和巨噬细胞)中，比TREM2更有益的功能。 我们还观察到TREM2在骨髓来源的基质细胞(BMSCs)中表达上调 暴露于实验性中风的小鼠的移植。实验室和实验室的最新研究 临床试验的重点是使用骨髓间充质干细胞来改善中风的预后，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，输送骨髓间充质干细胞 从野生型小鼠中提取并移植到TREM2缺陷小鼠中可改善神经预后 实验性卒中后，这与移植后TREM2的上调有关 骨髓间充质干细胞。我们还注意到，TREM2缺乏导致M1增加(促炎，有害) 实验性卒中后的极化与未受损的野生型小鼠炎症反应的比较 TREM2。在目标1中，我们将确定骨髓间充质干细胞治疗的机制是否源于转化 或将这些细胞上调为表达TREM2的细胞，以及TREM2转移是否阳性 髓系细胞也可能改善神经学结果。在目标2中，我们将确定雌性小鼠是否 对这些干预做出类似的反应。然后，AIM 3将探索TREM2如何参与 骨髓间充质干细胞的有益作用以及是否需要将小胶质细胞和巨噬细胞极化为M2 (抗炎、有益)表型。 OMB编号0925-0001/0002(08/12版批准至2015年8月31日)页面续格式页面

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