Astrocyte-endothelial crosstalk after cerebral ischemia and hemorrhage

脑缺血和出血后星形胶质细胞-内皮细胞的串扰

• 批准号: 8316127
• 负责人: Eng H. Lo
• 金额: $ 37.49万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316127
• 关键词: Adherence; Adhesions; Astrocytes; Behavioral; Binding; Biological Assay; Blocking Antibodies; Brain; Brain hemorrhage; CD18 Antigens; Cell Adhesion; Cell Culture Techniques; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrum; Cicatrix; Complement; Conditioned Culture Media; Data; Dendrites; Endothelial Cells; Endothelium; Exercise; Extracellular Signal Regulated Kinases; Fibroblast Growth Factor 1; Filament; Gelatinase A; Glucose; HMGB1 Protein; HMGB1 gene; Hemoglobin; Hemorrhage; Histologic; Hydrogen Peroxide; Image; In Vitro; Inflammation; Injection of therapeutic agent; Integrins; Investigation; Ischemia; Ischemic Stroke; Knowledge; Lead; Lesion; Link; Maps; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Molecular; Mus; Neurological outcome; Neuronal Plasticity; Neurons; Nitric Oxide; Outcome; Oxygen; Pathway interactions; Patients; Phenotype; Proliferating; Publishing; Recovery; Recovery of Function; Research; Role; Running; Signal Pathway; Signal Transduction; Small Interfering RNA; Stem cells; Stroke; Stromal Cell-Derived Factor 1; System; TLR2 gene; TLR4 gene; Techniques; Testing; Transgenic Mice; Traumatic Brain Injury; Tube; Vascular Endothelial Growth Factors; angiogenesis; base; central nervous system injury; collagenase; deprivation; improved; in vivo; inhibitor/antagonist; intercellular communication; migration; mouse model; neurological recovery; neutralizing antibody; novel; novel therapeutic intervention; optical imaging; post stroke; progenitor; receptor; receptor for advanced glycation endproducts; receptor upregulation; repaired; spatiotemporal; stroke recovery

DESCRIPTION (provided by applicant): Astrocyte-endothelial crosstalk after cerebral ischemia and hemorrhage Reactive astrocytes were traditionally thought to inhibit neuronal plasticity after CNS injury. But emerging data now suggest that reactive astrocytes may also have beneficial actions. Our pilot data suggest that (i) reactive astrocytes release HMGB1 that can promote angiogenesis, (ii) downregulating the release of HMGB1 from reactive astrocytes may worsen neurovascular recovery after focal ischemia in mice, (iii) HMGB1 may upregulate RAGE receptors on cerebral endothelial cells, (iv) increased endothelial RAGE may enhance targeted adhesion of endothelial progenitor cells via beta-2 integrins, and (v) HMGB1 may increase proliferation, maturation and angiogenesis in endothelial progenitor cells, thus promoting repair after stroke. Based on these pilot data, we hypothesize that astrocyte-endothelial crosstalk is essential for neurovascular recovery after stroke: reactive astrocytes release HMGB1 that upregulates RAGE receptor on cerebral endothelium; RAGE binds beta-2 integrins on circulating endothelial progenitor cells thus pulling them into recovering brain; and once endothelial progenitors arrive, HMGB1 promotes their proliferation, maturation and angiogenesis. Importantly, we propose that this pathway can promote recovery after both ischemic or hemorrhagic strokes. We will test this hypothesis in three aims. In Aim 1, we ask how HMGB1 from stimulated astrocytes upregulate RAGE on cerebral endothelial cells and enhance the targeted adhesion of endothelial progenitor cells. In Aim 2, we dissect mechanisms that underlie the ability of HMGB1 to enhance proliferation, maturation and angiogenesis in endothelial progenitor cells. In Aim 3, we will use mouse models of focal cerebral ischemia and intracerebral hemorrhage to confirm these astrocyte-endothelium-EPC mechanisms and show that they actually mediate neurovascular recovery in vivo. To test our pathways, we will use a combination of cell culture, in vivo mouse models, pharmacologic inhibitors, molecular techniques including siRNA, long-term neurological outcomes, and in vivo imaging. This study should define a novel mechanism wherein crosstalk between reactive astrocytes, cerebral endothelium, and circulating endothelial progenitor cells underlie neurovascular recovery after cerebral ischemia and hemorrhage. Dissecting these cell-cell signaling pathways may lead to new therapeutic approaches for promoting functional recovery in patients after ischemic and hemorrhagic strokes.

描述（由申请人提供）：传统上认为，脑缺血和出血反应性星形胶质细胞后，星形胶质细胞 - 内皮串扰被认为会抑制中枢神经系统损伤后的神经元可塑性。但是，新兴的数据现在表明反应性星形胶质细胞也可能采取有益的作用。 Our pilot data suggest that (i) reactive astrocytes release HMGB1 that can promote angiogenesis, (ii) downregulating the release of HMGB1 from reactive astrocytes may worsen neurovascular recovery after focal ischemia in mice, (iii) HMGB1 may upregulate RAGE receptors on cerebral endothelial cells, (iv) increased endothelial RAGE may enhance targeted内皮祖细胞通过β-2整联蛋白和（v）HMGB1的粘附可能会增加内皮祖细胞中内皮细胞的增殖，成熟和血管生成，从而促进中风后修复。基于这些试验数据，我们假设星形胶质细胞 - 内皮串扰对于中风后的神经血管恢复至关重要：反应性星形胶质细胞释放HMGB1，该HMGB1上调大脑内皮上的愤怒受体。愤怒将β-2整合素结合在循环的内皮祖细胞上，从而将其拉入大脑。一旦内皮祖细胞到达，HMGB1就会促进它们的增殖，成熟和血管生成。重要的是，我们建议该途径可以在缺血或出血性中风后促进恢复。我们将以三个目标检验这一假设。在AIM 1中，我们询问来自刺激的星形胶质细胞的HMGB1如何上调脑内皮细胞上的愤怒，并增强内皮祖细胞的靶向粘附。在AIM 2中，我们剖析了HMGB1增强内皮祖细胞增殖，成熟和血管生成能力的机制。在AIM 3中，我们将使用局灶性脑缺血和脑出血的小鼠模型来确认这些星形胶质细胞 - 内皮 - EPC机制，并表明它们实际上介导了体内神经血管恢复。为了测试我们的途径，我们将使用细胞培养，体内小鼠模型，药理学抑制剂，包括siRNA，长期神经学结果和体内成像在内的分子技术的组合。这项研究应定义一种新的机制，其中反应性星形胶质细胞，脑内皮和循环内皮祖细胞之间的串扰是脑缺血和出血后神经血管恢复的基础。解剖这些细胞 - 细胞信号传导途径可能会导致新的治疗方法，用于促进缺血性和出血性中风后患者的功能恢复。