AIF1/Iba1 in microglial function and stroke

摘要 每年，美国有近80万人罹患中风，这是导致 死亡率和导致残疾的主要可预防原因。这些事件中的大多数是 首次中风，近90%的中风可归类为缺血性中风 病因学。当血栓或肿块阻塞供血动脉的一部分时，就会发生这种中风。 大脑，切断血液流动，经常导致永久性神经元损伤。 小胶质细胞是巨噬细胞谱系中驻留在脑内的细胞，在 对各种刺激和损伤的反应，包括缺血性中风。在激活后， 小胶质细胞经历形态变化，增加标记的表达，包括 CD68和主要组织相容性复合体II类，并产生促炎作用 细胞因子，如肿瘤坏死因子-ɑ和白介素6(IL-6)。已激活 除中风外，小胶质细胞在许多脑部疾病中也普遍可见，包括 阿尔茨海默氏症和帕金森氏症，并被认为是神经- 发炎。小胶质细胞的激活如何影响脑损伤是复杂的，因为它们可以 调节有益和有害的影响，通过移除 通过吞噬过程的凋亡细胞和碎片，或可能导致损伤 通过它们的促炎活动。 同种异体移植物炎症因子-1(AIF1，又称IBA1)是一个高度保守的17kD 钙结合蛋白在小胶质细胞中表达，并在神经损伤后上调。 虽然AIF1/IBA1被广泛用作小胶质细胞的标志物，但其在 小胶质细胞的动态平衡和激活还不是很清楚。我们已经产生了这两个 灭活小鼠AIF1/IBA1表达的全局和条件等位基因；初步 研究表明，在缺乏AIF1/IBA1的小鼠中，中风损伤的面积明显更大。在这 建议，我们将使用功能丧失研究来评估在体内的贡献 AIF1/Iba1对小胶质细胞的基本功能，如迁移和吞噬功能，这些功能是 对神经损伤的反应很重要。我们还将确定AIF1/IBA1的损失 影响缺血性中风小鼠模型的体内综合反应。这些 研究将增加我们对小胶质细胞在中风康复中的功能的理解，以及 描述在这种情况下AIF1/IBA1如何促进恢复。

Abstract Every year, nearly 800,000 people in the United States suffer a stroke, a major cause of mortality and the leading preventable cause of disability. Most of these incidents are first-time strokes, and nearly 9 out of 10 strokes can be classified as ischemic in etiology. Such strokes occur when a clot or a mass blocks an artery supplying part of the brain, cutting off blood flow and often leading to permanent neuronal injury. Microglia are brain-resident cells of the macrophage lineage that activate rapidly in response to a variety of stimuli and injuries, including ischemic stroke. Upon activation, microglia undergo morphological changes, increase expression of markers including CD68 and major histocompatibility complex class II, and produce pro-inflammatory cytokines such as tumor necrosis factor-ɑ (TNF-ɑ) and interleukin-6 (IL-6). Activated microglia are commonly observed in many brain diseases in addition to stroke, including Alzheimer's and Parkinson's diseases, and are regarded as key mediators of neuro- inflammation. How microglial activation affects brain injury is complex, since they can mediate both beneficial and detrimental effects, protecting neurons by removing apoptotic cells and debris via phagocytic processes, or potentially contributing to injury through their pro-inflammatory activities. Allograft inflammatory factor-1 (AIF1, also known as Iba1) is a highly conserved 17kD Ca2+ binding protein expressed in microglia and upregulated in response to neural injury. While AIF1/Iba1 is widely used as a marker of microglia, its specific contributions to microglia homeostasis and activation are not well understood. We have generated both global and conditional alleles to inactivate AIF1/Iba1 expression in mice; preliminary studies suggest notably larger areas of stroke injury in mice lacking AIF1/Iba1. In this proposal, we will use loss of function studies to assess the in vivo contribution of AIF1/Iba1 to basic microglial functions, such as migration and phagocytosis, which are important for response to neural injury. We will also determine how loss of AIF1/Iba1 affects the integrated in vivo response in a mouse model of ischemic stroke. These studies will add to our understanding of microglial function in stroke recovery, and characterize how AIF1/Iba1 contributes to recovery in this setting.