Protective monocytes in cerebral ischemic tolerance

项目摘要/摘要 中风是一种流行的、毁灭性的疾病，治疗选择有限。炎症和 免疫细胞是缺血性卒中病理生理学的主要组成部分，在急性脑梗塞中起重要作用。 和延迟性组织损伤。然而，我们对免疫调节因素的了解还不够全面 脑缺血引发的反应仍然是发展有效的 基于调节缺血后炎症的治疗干预。除了激活大脑之外 常驻免疫细胞，缺血性卒中的特点是外周血与生俱来和 参与炎症反应并造成损害的适应性免疫细胞。 单核细胞来源的巨噬细胞是细胞先天免疫反应的主要组成部分 到缺血性中风。脑缺血后早期对缺血灶和周围区的渗透 并在受伤的领土上长期居住。这些观察结果提出了一种可能性 MM？有助于炎症从开始到消退的整个过程，具有潜在的 调节脑缺血损伤的转归。这项研究计划的长期目标是 阐明MM？在卒中病理生理学中的作用并建立新的实验框架。 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 脑缺血区存在MM？的假设在功能上和分子上是不同的 组织缺氧是多发性骨髓瘤分化和分化的重要决定因素 揭示了它们的神经保护能力。这一假说得到了相关初步结果的支持， 将通过确定：(A)MM？从单核细胞到长期常驻免疫的转变来进行测试 脑缺血后的细胞(目标1)，(B)低氧环境对组织分布的影响 以及(C)缺氧诱导因子1α(α)和糖酵解的作用 脑浸润性MM的功能极化代谢及其对卒中预后的影响 (目标3)。这些目标将通过使用短暂性局灶性脑缺血的小鼠模型来实现 组织学和神经学结果的评估以及一种新的脑分类模型 Mm？这项建议可能会为中风的预防和治疗开辟新的途径 MM？及其前体外周血单核细胞的调节。

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.