Protective monocytes in cerebral ischemic tolerance

脑缺血耐受中的保护性单核细胞

• 批准号: 10220141
• 负责人: Josef Anrather
• 金额: $ 37.08万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220141
• 关键词: Acute; Address; Affect; Anti-Inflammatory Agents; Biochemical; Blood; Blood Vessels; Blood flow; Brain; Brain Injuries; Cell Differentiation process; Cell Separation; Cells; Cerebral Ischemia; Cerebrum; Cessation of life; Classification; Clinical Trials; Cues; Dendritic Cells; Descriptor; Development; Disease; Drug or chemical Tissue Distribution; Environment; Functional disorder; Genes; Genetic; Goals; Histologic; Human; Hypoxia; Hypoxia Inducible Factor; Immune; Immune response; Immune system; In Situ; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Lesion; Metabolic Pathway; Metabolism; Methods; Microglia; Modeling; Molecular; Molecular Profiling; Monitor; Morphology; Myelogenous; Myeloid Cells; Neurological outcome; Nitric Oxide; Outcome; Oxygen; Pathogenesis; Pathologic Processes; Pathway interactions; Peripheral; Phenotype; Play; Population; Prevention therapy; Process; Reactive Oxygen Species; Research; Resistance; Resolution; Rodent; Rodent Model; Role; Signal Transduction; Stroke; Stroke prevention; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Tumor-infiltrating immune cells; base; brain cell; cell type; cerebral ischemic injury; chemokine; combinatorial; cytokine; disability; in vivo; injured; insight; interest; ischemic lesion; macrophage; monocyte; mouse model; neuronal survival; neutrophil; novel; novel strategies; peripheral blood; programs; recruit; repaired; response; single-cell RNA sequencing; stroke outcome; stroke patient; success; therapeutically effective; tissue injury; tissue oxygenation; transcription factor; transcriptome

Project Summary/Abstract Stroke is a prevalent and devastating disease with limited therapeutic options. Inflammation and immune cells are major components in the pathophysiology of ischemic stroke and contribute to acute and delayed tissue injury. However, our incomplete understanding of the factors regulating the immune responses triggered by cerebral ischemia remains a significant obstacle to the development of effective therapeutic interventions based on modulating post-ischemic inflammation. Besides activation of brain resident immune cells, ischemic stroke is characterized by the recruitment of peripheral innate and adaptive immune cells that participate in the inflammatory response and contribute to the damage. Monocyte-derived macrophages (MMØ) are a major component of the cellular innate immune response to ischemic stroke. MMØ infiltrate the ischemic lesion and perilesional territories early after ischemia and reside in the injured territory for prolonged periods of time. These observations raise the possibility that MMØ contribute to the entire inflammatory process from initiation to resolution with the potential of modulating the outcome of cerebral ischemic injury. The long-term goal of this research program is to elucidate the role of MMØ in stroke pathophysiology and develop the experimental framework for new preventative and therapeutic approaches for ischemic stroke. In the present application, we will test the hypothesis that MMØ are present in the ischemic territory as functionally divergent and molecularly definable populations and that tissue hypoxia is an important determinator for MMØ differentiation and revelation of their neuroprotective capacity. This hypothesis, supported by relevant preliminary results, will be tested by determining: (a) the transition of MMØ from monocytes to long-term resident immune cells in the post-ischemic brain (Aim 1), (b) the effects of the hypoxic environment on tissue distribution and polarization of MMØ (Aim 2), and (c) the role of hypoxia-inducible factor 1α (HIF1α) and glycolytic metabolism in the functional polarization of brain-infiltrating MMØ and their effects on stroke outcome (Aim 3). These goals will be achieved using a mouse model of transient focal cerebral ischemia with assessment of histological and neurological outcome together with a novel model for classifying brain MMØ. This proposal may open the way to new avenues for stroke prevention and therapy based on modulation of MMØ and their precursor, the peripheral blood monocyte.

项目摘要/摘要 中风是一种普遍的毁灭性疾病，治疗选择有限。发炎和 免疫细胞是缺血性中风病理生理学中的主要成分，并导致急性 并延迟组织损伤。但是，我们对调节免疫的因素的不完全理解 脑缺血引起的反应仍然是发展有效的重要障碍 基于调节缺血后炎症的治疗干预措施。除了大脑激活 居民免疫小球，缺血性中风的特征是招募外围先天和 参与炎症反应并导致损害的自适应免疫细胞。 单核细胞衍生的巨噬细胞（MMø）是细胞先天免疫响应的主要组成部分 Mmø浸润缺血性病变和周围区域早期缺血后 并居住在受伤的领土上长时间。这些观察提出了可能性 MMø为从启动到解决方案的整个炎症过程有助于 调节脑缺血性损伤的结果。该研究计划的长期目标是 阐明MMø在中风病理生理学中的作用并开发新的实验框架 缺血性中风的预防和治疗方法。在本应用程序中，我们将测试 假设Mmø存在于功能上的分歧和分子上存在于缺血区域 可确定的人群，组织缺氧是MMø分化和 其神经保护能力的启示。该假设得到了相关初步结果的支持 将通过确定：（a）从单核细胞到长期居民免疫的过渡来测试：（a） 缺血后大脑中的细胞（AIM 1），（b）缺氧环境对组织分布的影响 MMø（AIM 2）的极化，以及（c）缺氧诱导因子1α（HIF1α）和糖酵解的作用 脑浸润MMø的功能极化及其对中风结果的影响 （目标3）。使用瞬态局灶性脑缺血的鼠标模型将实现这些目标 评估组织学和神经系统结果以及用于分类大脑的新型模型 mmø。该建议可能为基于中风的新途径开辟了道路。 MMø及其前体的调节，外周血单核细胞。