Modulating Monocyte Responses to Reduce Injury after Intracerebral Hemorrhage

调节单核细胞反应以减少脑出血后的损伤

• 批准号: 8772759
• 负责人: LAUREN H SANSING
• 金额: $ 24.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772759
• 关键词: Address; Affect; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood specimen; Bone Marrow; Brain; Brain Injuries; CCL22 gene; CD36 gene; Caring; Cell surface; Cells; Cerebral hemisphere hemorrhage; Chimera organism; Clinical; Data; Development; Environment; Event; Exhibits; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Fibrinogen; Functional disorder; Future; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Hematoma; Hematopoietic; Heme; Hemorrhage; Hour; Human; Immune; Immune system; Incubated; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interferons; Interleukin-4; Knowledge; Leukocytes; Life; Link; Literature; Macrophage Colony-Stimulating Factor; Mediator of activation protein; Medical; Minor; Modeling; Mus; Outcome; PTPNS1 gene; Patients; Peripheral; Peroxisome Proliferator-Activated Receptors; Phagocytosis; Phase; Phenotype; Plasma; Production; Recombinant Proteins; Recovery; Resolution; Rodent Model; Role; Sampling; Signal Pathway; Signal Transduction; Site; Stimulus; Stroke; Surface; TNF gene; Therapeutic; Thrombin; Time; Tissues; Transforming Growth Factors; Work; base; brain repair; chemokine; cytokine; improved; macrophage; monocyte; motor deficit; new therapeutic target; novel; novel strategies; pathogen; pre-clinical; public health relevance; receptor; repaired; research study; response; tissue repair

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is a devastating type of stroke affecting more than 2 million patients worldwide each year, yet there is no specific treatment available. Activation of the innate immune system at the site of hemorrhage leads to monocyte recruitment to the brain and progressive injury. In a murine model of ICH, the PI has demonstrated that the recruitment of blood-derived inflammatory monocytes to the perihematomal region leads to significant injury in the first days after ICH. However, over time, these cells contribute to phagocytosis and recovery. Interestingly, modulation of monocyte responses to inflammatory stimuli may occur in the periphery, while the monocytes are circulating and have not yet entered the brain. Whether this occurs in ICH is not known. In other models, priming by cytokines and growth factors determine whether monocytes will develop M1, proinflammatory responses, or M2 responses associated with phagocytosis and repair in response to an inflammatory environment. We propose the novel hypothesis that monocyte responses to ICH can be modulated in the systemic circulation in order to minimize early, inflammation-induced injury and expedite the recovery phase. The proposed R21 Award studies follow directly from this pre-clinical work. We will examine the effect of priming of human monocytes with inflammatory cytokines and growth factors elevated in the circulation of ICH patients on the effector responses of those cells to an inflammatory stimulus. We hypothesize that priming with interleukin-4 (IL-4) will result in enhanced phagocytosis and reduced expression of pro-inflammatory mediators (M2 response). This work will include both monocytes from both healthy controls and patients with ICH in order to maximize translational relevance. This represents a novel strategy for reducing injury after ICH, and would obviate the need for a potential therapeutic to cross the blood-brain barrier. This exploratory work will determine whether therapeutic strategies that modulate monocyte responses have the potential to improve outcomes after ICH.

描述（由申请人提供）：脑内出血（ICH）是一种毁灭性的中风类型，每年影响全球超过200万名患者，但没有特定的治疗方法。在出血部位激活先天免疫系统会导致大脑的单核细胞募集和进行性损伤。在ICH的鼠模型中，PI表明，募集血液来源的炎症单核细胞向近日 - 成amapotomal区域导致ICH后的头几天导致重大损伤。但是，随着时间的流逝，这些细胞有助于吞噬作用和恢复。有趣的是，单核细胞对炎症性刺激的反应调节可能发生在外围，而单核细胞循环且尚未进入大脑。这是否发生在ICH中是不清楚的。在其他模型中，细胞因子和生长因子的启动决定了单核细胞是否会产生M1，促炎反应或与吞噬作用和修复有关的M2反应，以响应炎症环境。我们提出了一个新的假设，即可以在全身循环中调节单核细胞对ICH的反应，以最大程度地减少早期炎症引起的损伤并加快恢复阶段。 拟议的R21奖项研究直接来自这项临床前的工作。我们将研究人类启动的效果 ICH患者的循环中这些细胞对这些细胞对炎症刺激的效应子反应的循环中的炎性细胞因子和生长因子的单核细胞升高。我们假设用白介素4（IL-4）启动会导致吞噬作用增强和促炎性介体的表达降低（M2反应）。这项工作将包括来自健康对照的单核细胞和ICH患者，以最大程度地提高转化相关性。这代表了减少ICH后减少损伤的新策略，并消除了潜在的治疗性越过血脑屏障的必要性。这项探索性工作将决定调节单核细胞反应的治疗策略是否有可能改善ICH后的结果。