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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：多年来，中枢神经系统（CNS）被认为是免疫特你的器官。但是，现在越来越怀疑大脑和全身反应之间的串扰在中枢神经系统疾病中起关键作用。这可能在中风中尤其重要，在大脑缺血或出血后发生炎性血细胞的浸润。特别是，单核细胞/巨噬细胞（M-theta）被认为担心脑损伤。在此K99应用程序中，我们提出了一个新想法，即M-Theta细胞并不总是损害。相反，根据时间和表型，这些细胞还可以诱导有益的神经血管重塑。这是理解所涉及的机制可能使我们能够控制促进脑修复和中风恢复的M theta表型。为了检验我们的假设，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与新型生物材料和体内光学成像结合在一起。我们的最终目标是通过控制M-THETA细胞的有益表型来定义增强“大脑重塑”的新机制。 Our pilot data are intriguing: (i) M-theta cells release IL-1B after HMGB1 (DAMP) simulation, 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 receiver 4 (TLR4)high /Flk1low M-theta to LPS刺激后TLR4LOW/FLK1HIGH M- tHETA，（III）CD34+/FLK1+细胞与单核细胞区分开可能会诱导血管生成和在体外的血管生成和不成熟的神经元在体外（IV）早期使用CD200FC的早期治疗可能会增加CD34+/FLK1+/FLK1+/FLK1+/FLRR4LWOW-flk1high-y-ligh-lighigh-y-lighigh-yigh-yigh-yigh-m。小鼠脑缺血后，神经胶质和改善神经元可塑性。我们将基于我们的试验数据，以定义大脑反应性星形胶质细胞和全身循环单核细胞细胞之间的串扰机制。我们的假设是两个方面：（1）星形胶质细胞CD200将单核细胞/m theta表型从有害变为有益。（2）调节CD200-CD200R信号通路可能会导致新的治疗方法，以通过“全身调制”在广泛的CNS疾病后促进“大脑重塑”。我已经在细胞培养和体内模型中发表了经验。我将从我的心理/顾问那里学习生物材料和体内光学成像工具。我的长期目标是基于操纵感染以进行脑修复的主题而成长和建立我的独立实验室。