LEUKOCYTE ADHESION AND CNS ISCHEMIC INJURY

白细胞粘附和中枢神经系统缺血性损伤

• 批准号: 2259345
• 负责人: WAYNE M CLARK
• 金额: $ 9.37万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-15 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2259345
• 关键词: antibody; central nervous system; cerebral ischemia /hypoxia; disease /disorder model; drug adverse effect; immunotherapy; laboratory rabbit; leukocyte adhesion molecules; model design /development; monoclonal antibody; neutrophil; nonhuman therapy evaluation; surface antigens

The training and research program outlined in this proposal supports the application for an NINDS Clinical Investigator Development Award for Dr. Wayne Clark. The proposed project will enable Dr. Clark to develop, under the direct supervision of Dr. Bruce Coull, into a well trained researcher with an expertise in cerebrovascular disease. The overall objective of the research proposed for the five year period of the award is to investigate the role of leukocyte adhesion in CNS ischemic injury. The experiments proposed are based on three major hypotheses supported by previous studies: 1) that leukocytes are active participants in neuronal ischemic injury; 2) that their involvement requires leukocyte adhesive properties; and, 3) that their adverse effects can be reduced by using a new therapy, leukocyte anti-adhesion antibody (anti-CD 18). The two main objectives of this CIDA application are to 1) study the relationship between leukocytes and CNS ischemia and 2) determine if leukocyte anti-adhesion antibody treatment is effective in reducing CNS injury. To accomplish these objectives, the following experiments are proposed: Leukocyte rheologic properties will be measured using filtration techniques. Using a model of selective experimental CNS ischemia, a repeated measures design will be used to compare baseline rheologic measurements to results obtained in ischemic animals with or without anti-CD 18 treatment. The timing and extent of leukocyte infiltration into ischemic CNS tissue will be assessed using an experimental CNS ischemia model. Direct histologic evaluation will compare ischemic animals with or without anti-CD 18 treatment. The therapeutic efficacy of anti-CD 18 treatment will be assessed in an experimental reversible large vessel CNS ischemia model. This model will test the ability of anti-CD 18 to reduce reperfusion injury (no reflow phenomenon). The therapeutic efficacy of anti-CD 18 treatment will be assessed in an experimental irreversible microvascular CNS ischemia model. This model will test the ability of anti-CD 18 to improve blood flow to the ischemic penumbra. The results from the above studies are expected to confirm the active role of leukocytes in exacerbating CNS ischemic injury. If anti-CD 18 treatment is effective at reducing CNS reperfusion injury, it offers tremendous potential as a clinical stroke therapy, particularly given the current clinical use of thrombolytic agents.

本提案中概述的培训和研究方案支持 申请NINDS临床研究者发展奖。 韦恩克拉克。拟议的项目将使克拉克博士能够在 布鲁斯库尔博士的直接指导下，成为一个训练有素的研究人员 在脑血管疾病方面有专长 五年期研究的总体目标是： 该奖项旨在研究白细胞粘附在中枢神经系统缺血性疾病中的作用， 损伤所提出的实验基于三个主要假设 先前的研究支持：1）白细胞是活跃的参与者 在神经元缺血性损伤中; 2）它们的参与需要白细胞 粘合性能;以及，3）它们的不利影响可以通过以下方式减少： 使用一种新的疗法，白细胞抗粘附抗体（抗CD 18）。两 本CIDA应用程序的主要目标是1）研究关系 白细胞和CNS缺血之间的关系，以及2）确定白细胞是否 抗粘附抗体治疗可有效减少CNS损伤。到 为了实现这些目标，建议进行以下实验： 将使用过滤法测量白细胞流变学特性 技术.使用选择性实验性CNS缺血模型， 将使用重复测量设计比较基线流变学 测量结果与缺血性动物中获得的结果相比， 抗CD 18治疗。 缺血性CNS组织中白细胞浸润的时间和程度 将使用实验性CNS缺血模型进行评估。直接 组织学评价将比较有或没有抗CD的缺血动物 18治疗 抗CD 18治疗的疗效将在一项研究中评估。 实验性可逆性大血管CNS缺血模型。这种模式的 测试抗CD 18减少再灌注损伤（无复流）的能力 现象）。 抗CD 18治疗的疗效将在一项研究中评估。 实验性不可逆微血管CNS缺血模型。这种模式的 测试抗CD 18改善缺血性血管的血流的能力， 半影 上述研究的结果有望证实 白细胞在加重CNS缺血性损伤中的作用。如果抗CD 18治疗 有效减少CNS再灌注损伤， 作为临床中风治疗的潜力，特别是考虑到目前 溶栓药物的临床应用。