AIF1/Iba1 in microglial function and stroke

AIF1/Iba1 在小胶质细胞功能和中风中的作用

• 批准号: 10057671
• 负责人: Sayan Nandi
• 金额: $ 44.06万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057671
• 关键词: Abbreviations; Actins; Affect; Alleles; Alzheimer' s Disease; Analysis of Variance; Anti-Inflammatory Agents; Apoptotic; Area; Arteries; Astrocytes; Axotomy; Binding; Binding Proteins; Biology; Blood flow; Body part; Bone Marrow; Brain; Brain Diseases; Brain Injuries; Bundling; Cells; Chlorides; Coagulation Process; Complex; Data; Databases; Enterobacteria phage P1 Cre recombinase; Enzyme-Linked Immunosorbent Assay; Etiology; Exhibits; External carotid artery structure; Gene Expression; Generations; Glial Fibrillary Acidic Protein; Goals; Histocompatibility Antigens Class II; Histologic; Histone H3; Homeostasis; Immunohistochemistry; In Vitro; Inflammatory; Injury; Integral Membrane Protein; Interleukin-6; Interleukins; Internal carotid artery structure; Interruption; Intervention; Ions; Ischemia; Ischemic Stroke; Isolectin; Lead; Link; Malnutrition; Mediating; Mediator of activation protein; Methods; Microglia; Microtubule-Associated Protein 2; Middle Cerebral Artery Occlusion; Modeling; Morphology; Mus; N-Methylaspartate; NOS3 gene; Neuraxis; Neurologic; Neuronal Injury; Neurons; Nutrient; Oxygen; Parkinson Disease; Pathologic; Phagocytes; Phagocytosis; Plasminogen Activator Inhibitor 1; Prevention; Process; Production; Property; Proteins; Purinoceptor; RNA Splicing; Reaction; Recovery; Recovery of Function; Reperfusion Injury; Role; Severities; Stimulus; Stroke; TNF gene; Tamoxifen; Testing; Time; Tissues; Transcript; United States; Vascular Cell Adhesion Molecule-1; Visualization; allograft inflammatory factor-1; astrogliosis; base; brain tissue; cell injury; cell motility; cytokine; disability; experimental study; improved; in vivo; injured; loss of function; macrophage; migration; mortality; mouse model; nerve injury; neuroinflammation; neurological recovery; post stroke; response; response to brain injury; stroke recovery; stroke therapy; tissue injury; transcription factor

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.

抽象的 每年，美国近80万人中风，这是一个主要原因 死亡率和主要可预防的残疾原因。这些事件大多是 首次中风，十分之九的中风可以归类为缺血性 病因。当凝块或质量阻塞动脉提供一部分的动脉时，就会发生这种情况 大脑，切断血液流动，通常导致永久性神经元损伤。 小胶质细胞是巨噬细胞谱系的脑居民细胞，可快速激活 对各种刺激和伤害的反应，包括缺血性中风。激活后， 小胶质细胞经历形态变化，增加标记的表达 CD68和主要的组织相容性复合物II类，并产生促炎性 细胞因子（例如肿瘤坏死因子）（TNF-E）和白介素6（IL-6）。活性 除了中风，包括 阿尔茨海默氏症和帕金森氏症的疾病，被认为是神经神经的关键调解人 炎。小胶质细胞激活如何影响脑损伤是复杂的，因为它们可以 介导有益和有害效果，通过去除神经元来保护神经元 凋亡细胞和碎屑通过吞噬过程，或可能导致损伤 通过他们的促进活动。 Alllograft炎症因子1（AIF1，也称为IBA1）是高度保守的17KD Ca2+结合蛋白在小胶质细胞中表达，并响应神经损伤而更新。 虽然AIF1/iba1被广泛用作小胶质细胞的标记，但其对 小胶质细胞稳态和激活尚不清楚。我们已经产生了 全局和条件等位基因使小鼠中的AIF1/IBA1表达灭活；初步的 研究表明，在缺乏AIF1/IBA1的小鼠中，中风损伤的区域明显更大。在这个 提案，我们将利用功能研究的损失来评估体内贡献 aif1/iba1至基本的小胶质细胞功能，例如迁移和吞噬作用， 对于对神经损伤的反应很重要。我们还将确定AIF1/IBA1的损失 在缺血性中风的小鼠模型中影响体内综合反应。这些 研究将增加我们对中风恢复中小胶质功能的理解，以及 表征AIF1/IBA1在这种情况下如何贡献恢复。