Inflammatory mechanisms in cerebral ischemia

脑缺血的炎症机制

• 批准号: 8254475
• 负责人: Midori A Yenari
• 金额: $ 31.77万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254475
• 关键词: Adaptor Signaling Protein; Affect; Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Astrocytes; Bacteria; Binding; Bone Marrow; Brain; Brain Ischemia; Cells; Cerebral Ischemia; Chimera organism; Dendritic Cells; Eukaryotic Cell; Experimental Models; Family; Functional disorder; Immune; Immune system; In Vitro; Inflammation; Inflammatory; Injury; Ischemia; Knockout Mice; Knowledge; Lead; Lesion; Ligands; Marrow; Mediating; Microglia; Modeling; Mus; Myeloid Cells; Necrosis; Nerve Degeneration; Neurologic; Neurological outcome; Neurons; Osteoclasts; Outcome; Pathway interactions; Phagocytosis; Principal Investigator; Process; Property; Proteins; Reaction; Recovery; Signal Transduction; Small Interfering RNA; Stroke; TYROBP gene; Tissues; Transplantation; Up-Regulation; abstracting; brain cell; brain tissue; cell type; effective therapy; improved; in vitro Model; in vivo; injured; macrophage; monocyte; novel; prevent; programs; receptor; regenerative; response

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

项目负责人/主要研究者（最后，第一，中间）：Yenari，Midori A 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 清除坏死的碎片并启动再生过程。表达的触发受体 髓样细胞-2（TREM2）是最近发现的参与先天免疫系统的受体。 TREM2与细菌和真核细胞以及受损的神经元结合。TREM2也是 在小胶质细胞上表达，在那里它似乎促进受损神经元的吞噬作用。我们有 初步发现脑缺血后小胶质细胞上TREM2表达上调， 其配体存在于神经元和星形胶质细胞上。TREM2似乎也具有抗- 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通过促进缺血性脑细胞的吞噬作用来限制中风引起的损伤， 免疫分子表达。在目标1中，我们将确定TREM2缺陷是否导致 在实验性中风和缺血样损伤后， 信号传导发生在缺血组织中。在目标2中，我们将确定TREM2是否以及如何参与 在介导小胶质细胞功能，如吞噬缺血后受损的神经元， 侮辱。使用缺血样损伤的体外模型，我们将确定TREM2是否参与了 受损神经元的吞噬作用，以及TREM2敲低或其抑制是否会阻止这种吞噬作用。 在目标3中，我们将确定TREM2功能的贡献，由于脑驻留（小胶质细胞）或 循环（巨噬细胞）骨髓细胞通过利用中风的骨髓嵌合体模型。我们 总体假设是TREM2对于吞噬受损脑细胞是必不可少的， 损伤组织的清除对于改善中风的结果是至关重要的。我们希望我们的研究 将建立在我们对炎症性脑反应对缺血的重要性的认识上。 PHS 398/2590（Rev. 11/07）