CD200 as a monocyte/macrophage switch for brain repair after stroke

CD200作为单核细胞/巨噬细胞开关用于中风后的脑修复

• 批准号: 8578114
• 负责人: Kazuhide Hayakawa
• 金额: $ 9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578114
• 关键词: Acute; Astrocytes; Behavioral; Biocompatible; Biocompatible Materials; Biological Assay; Blood Cells; Brain; Brain Injuries; Brain hemorrhage; CD 200; CD34 gene; Cell Culture Techniques; Cell Lineage; Cells; Cellular biology; Central Nervous System Diseases; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Coculture Techniques; Complement; Conditioned Culture Media; Data; Early treatment; Enzyme-Linked Immunosorbent Assay; Gliosis; Glucose; Goals; Greater sac of peritoneum; HMGB1 gene; Heat shock proteins; Hemoglobin; Hemorrhage; Histologic; Hydrogen Peroxide; IL1R1 gene; Image; Imaging Device; Immune; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Lead; Learning; M cell; MAPK8 gene; Maps; Measures; Mentors; Modeling; Molecular; Molecular Biology; Mononuclear; Mus; Neuraxis; Neurological outcome; Neuronal Plasticity; Neurons; Organ; Oxygen; Pathway interactions; Pattern; Peritoneal; Pharmacology; Phase; Phenotype; Plasma; Play; Publishing; Rattus; Recombinant Interleukin-1; Research Training; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Spleen; Stem cells; Stroke; System; Techniques; Testing; Time; Transgenic Mice; Western Blotting; angiogenesis; base; brain remodeling; brain repair; cell type; deprivation; experience; improved; in vivo; in vivo Model; inhibitor/antagonist; macrophage; mitogen-activated protein kinase p38; monocyte; neurogenesis; neutralizing antibody; novel; novel therapeutic intervention; optical imaging; public health relevance; receptor; research study; response; scaffold; spatiotemporal; stroke recovery; toll-like receptor 4

DESCRIPTION (provided by applicant): For many years, the central nervous system (CNS) was considered an immune-privileged organ. However, crosstalk between the brain and systemic responses is now increasingly suspected of playing critical roles in CNS disease. This may be especially important in stroke, where infiltration of inflammatory blood cells takes place after cerebral ischemia or hemorrhage. In particular, monocytes/macrophages (M-theta) are thought to worsen brain injury. In this K99 application, we propose the new idea that M-theta cells are not always damaging. Instead, depending on timing and phenotype, these cells can also induce beneficial neurovascular remodeling. Thus, understanding the mechanisms involved may allow us to control M-theta phenotype for promoting brain repair and stroke recovery. To test our hypothesis, we will a multi-disciplinary approach, combining molecular and cell biology with in vivo pharmacology in transgenic mice together with novel biomaterials and in vivo optical imaging. Our ultimate goal is to define a new mechanism for enhancing "brain remodeling" by controlling the beneficial phenotype of M-theta cells. Our pilot data are intriguing: (i) M-theta cells release IL-1B after HMGB1 (DAMP) stimulation, and IL-1B enhances CD200 expression in reactive astrocytes, (ii) CD200 may induce monocyte phenotype into CD34+/Flk1+ cells and change M¿ phenotype from toll-like receptor 4 (TLR4)high /Flk1low M-theta to TLR4low/Flk1high M- theta after LPS stimulation, (iii) CD34+/Flk1+ cells differentiated from monocytes may induce angiogenesis and growing immature neuron in an in vitro, (iv) early treatment with CD200Fc may increase CD34+/Flk1+ cells and TLR4low/Flk1high M-theta in parallel with reducing massive gliosis and improving neuronal plasticity in peri-infarct cortex after cerebral ischemia in mice. We will build on our pilot data to define a mechanism of crosstalk between the brain reactive astrocyte and systemic circulating monocyte lineage cells. Our hypothesis is two-fold: (1) Astrocytic CD200 switches the monocyte/M-theta phenotype from harmful to beneficial. (2) Regulating CD200-CD200R signaling pathway may lead to new therapeutic approaches to promote "brain remodeling" via "systemic modulation" after a broad range of CNS diseases. I already have published experience in the cell culture and in vivo models. I will learn the biomaterials and in vivo optical imaging tools from my mentor/consultants. My long term goal is to grow and build my independent lab based on the theme of manipulating inflammation for brain repair.

描述(申请人提供)：多年来，中枢神经系统(CNS)被认为是免疫特权器官。然而，大脑和全身反应之间的串扰现在越来越被怀疑在中枢神经系统疾病中发挥关键作用。这在中风中可能尤其重要，因为在脑缺血或出血后，炎性血细胞会渗入。特别是，单核/巨噬细胞(M-theta)被认为会加重脑损伤。在K99的应用中，我们提出了M-theta细胞并不总是具有破坏性的新观点。相反，根据时间和表型的不同，这些细胞也可以诱导有益的神经血管重构。因此，了解其中涉及的机制可能使我们能够控制M-theta表型，促进大脑修复和中风的恢复。为了验证我们的假设，我们将采用多学科方法，将分子和细胞生物学与转基因小鼠的体内药理学、新型生物材料和体内光学成像相结合。我们的最终目标是定义一种新的机制，通过控制M-theta细胞的有益表型来增强“大脑重塑”。我们的初步数据很有趣：(I)M-theta细胞在HMGB1(DAMP)刺激后释放IL-1B，IL-1B增强反应性星形胶质细胞CD200的表达，(Ii)CD200可能诱导单核细胞表型为CD34+/Flk1+细胞，并在脂多糖刺激后将Mé表型从Toll样受体4(TLR4)高/Flk1低M-theta转变为TLR4low/Flk1高M-theta，(Iii)单核细胞分化为CD34+/Flk1+细胞可在体外诱导血管生成和生长未成熟神经元。(4)早期应用CD200Fc可能通过增加CD34+/Flk1+细胞和TLR4low/Flk1高M-theta，减少脑缺血后梗死灶周围皮质大量胶质细胞的增多，提高神经元的可塑性。我们将以我们的试点数据为基础，确定大脑反应性星形胶质细胞和系统循环单核细胞系细胞之间的串扰机制。我们的假设是双重的：(1)星形细胞CD200将单核细胞/M-theta表型从有害转变为有益。(2)调控CD200-CD200R信号通路可能为多种中枢神经系统疾病后通过“系统调节”促进“脑重塑”开辟新的治疗途径。我已经发表了在细胞培养和体内模型方面的经验。我将从我的导师/顾问那里学习生物材料和体内光学成像工具。我的长期目标是发展和建立我的独立实验室，以操纵炎症来修复大脑为主题。