Protective monocytes in cerebral ischemic tolerance

项目总结/摘要 中风是一种流行和毁灭性的疾病，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成分， 和延迟的组织损伤。然而，我们对调节免疫的因素的不完全理解， 由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 缺血性中风的特征是外周先天免疫细胞的募集， 适应性免疫细胞参与炎症反应并导致损伤。 单核细胞源性巨噬细胞（Monocyte-derived macrophages，MMCs）是细胞天然免疫反应的主要成分 缺血性中风脑缺血后早期，MMP-2浸润缺血灶及周围区域 并在受害国领土上长期居住。这些观察结果提出了一种可能性 MMPs参与了从开始到消退的整个炎症过程， 调节脑缺血性损伤的结果。这项研究计划的长期目标是 阐明MMPs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。在本申请中，我们将测试 假设MMPs在缺血区域中存在功能上的差异， 组织缺氧是MM细胞分化的重要决定因素， 揭示了它们的神经保护能力。这一假设得到了相关初步结果的支持， 将通过确定以下指标进行测试：（a）MMIL从单核细胞向长期驻留免疫细胞的转变 缺血后脑中的细胞（Aim 1），（B）缺氧环境对组织分布的影响 低氧诱导因子1α（HIF 1 α）和糖酵解的作用 脑浸润性MMPs功能极化中的代谢及其对卒中结局的影响 (Aim 3）。这些目标将使用短暂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脑分类的新模型 好吧这一建议可能会开辟新的途径，中风预防和治疗的基础上， MMPs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.