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

描述（由申请人提供）：多年来，中枢神经系统（CNS）被认为是一种免疫特权器官。然而，现在越来越多的人怀疑大脑和系统反应之间的串扰在中枢神经系统疾病中起着关键作用。这在脑缺血或出血后炎症血细胞浸润的中风中尤其重要。特别是单核细胞/巨噬细胞（M-theta）被认为会加重脑损伤。在这个K99应用程序中，我们提出了M-theta细胞并不总是破坏性的新想法。相反，根据时间和表型，这些细胞也可以诱导有益的神经血管重塑。因此，了解相关机制可能使我们能够控制M-theta表型以促进脑修复和中风恢复。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体内药理学结合起来，结合新型生物材料和体内光学成像。我们的最终目标是通过控制M-theta细胞的有益表型来定义一种增强“大脑重塑”的新机制。我们的试点数据很有趣：(1) 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中CD200的表达；(2)CD200诱导单核细胞表型转变为CD34+/Flk1+细胞，LPS刺激后M- β表型由toll样受体4 （TLR4）高/Flk1low M-theta转变为TLR4low/Flk1high M-theta； (3) CD34+/Flk1+细胞在体外诱导血管生成和未成熟神经元生长。（iv）早期应用CD200Fc可增加小鼠脑缺血后CD34+/Flk1+细胞和TLR4low/Flk1high M-theta，同时减少大量胶质细胞增生，改善梗死周围皮层神经元可塑性。我们将建立我们的试点数据，以确定脑反应星形胶质细胞和系统循环单核细胞谱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)调节CD200-CD200R信号通路可能为多种中枢神经系统疾病后通过“全身调节”促进“脑重塑”提供新的治疗途径。我已经发表了关于细胞培养和体内模型的经验。我将向我的导师/顾问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，以控制大脑修复炎症为主题。

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.