Inflammatory mechanisms in cerebral ischemia

项目主任/首席调查员(最后、第一、中间)：Yenari，Midori A 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，但可能在 清除坏死性碎片并启动再生过程。触发受体的表达 髓样细胞-2(TREM2)是新近发现的一种参与天然免疫系统的受体。 TREM2可与细菌、真核细胞以及受损神经元结合。TREM2也是 在小胶质细胞上表达，在那里它似乎促进了受损神经元的吞噬。我们有 初步发现脑缺血后小胶质细胞TREM2表达上调， 它的配体存在于神经元和星形胶质细胞上。TREM2似乎也有反 炎症特性，这可能会限制中风的一些破坏性影响。我们建议 TREM2通过促进缺血脑细胞的吞噬作用减少中风所致的损伤 免疫分子表达。在目标1中，我们将确定TREM2缺乏是否会导致 在实验性中风和缺血样侮辱后加重损伤，以及TREM2是否 信号发生在缺血组织中。在目标2中，我们将确定是否以及如何参与TREM2 在介导小胶质细胞功能方面，如吞噬类缺血后受损的神经元 侮辱。利用体外缺血样损伤模型，我们将确定TREM2是否参与了 受损神经元的吞噬作用，以及TREM2基因的敲除或抑制是否会阻止这一过程。 在目标3中，我们将确定由于大脑驻留(小胶质细胞)或 通过利用中风的骨髓嵌合体模型来循环(巨噬细胞)髓系细胞。我们的 最重要的假设是，TREM2对受损脑细胞的吞噬作用是必不可少的，而 清除损伤组织是改善中风预后的关键。我们希望我们的研究 将建立在我们对脑缺血炎症反应的重要性的知识基础上。 PHS 398/2590(11/07版)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): Yenari, Midori A 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 both bacteria and eukaryotic cells, as well as injured neurons. TREM2 is also expressed on microglia, where it appears to promote the phagocytosis of injured neurons. We have preliminarily found that expression of TREM2 on microglia is upregulated following brain ischemia, and its ligands are present on neurons and astrocytes. TREM2 also appears to have anti- inflammatory properties, which could limit some of the damaging effects of stroke. We propose that TREM2 limits injury due to stroke by promoting the phagocytosis of ischemic brain cells and reduces immune molecule expression. In Aim 1, we will determine whether TREM2 deficiency leads to worsened injury following experimental stroke and ischemia-like insults, and whether TREM2 signaling occurs in ischemic tissue. In Aim 2, we will determine whether and how TREM2 is involved in mediating microglial functions such as phagocytosing injured neurons following ischemia like insults. Using in vitro models of ischemia-like injury, we will determine whether TREM2 is involved in the phagocytosis of injured neurons, and whether TREM2 knockdown or its inhibition will prevent this. In Aim 3, we will determine the contributions of TREM2 functions due to brain resident (microglia) or circulating (macrophages) myeloid cells by utilizing a bone marrow chimera model of stroke. Our overarching hypothesis is thatTREM2 is essential for phagocytosis of injured brain cells, and the clearance of injured tissue is essential to improved outcome from stroke. We hope that our studies will build on our knowledge of the significance of the inflammatory brain response to ischemia. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page