EVALUATION OF ANTI-ADHESION MOLECULE THERAPY AFTER MCA OCCLUSION IN THE RAT

大鼠 MCA 闭塞后抗粘连分子治疗的评价

• 批准号: 6359002
• 负责人: MICHAEL CHOPP
• 金额: $ 17.32万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6359002
• 关键词: artery occlusion; autoradiography; bioimaging /biomedical imaging; blood brain barrier; brain circulation; cerebral artery; cerebrovascular disorder diagnosis; cerebrovascular imaging /visualization; cytotoxicity; diagnosis design /evaluation; disease /disorder model; immunotherapy; ischemia; laboratory rat; leukocyte adhesion molecules; magnetic resonance imaging; monoclonal antibody; neurophysiology; neutrophil; nonhuman therapy evaluation; noninvasive diagnosis; nuclear magnetic resonance spectroscopy; prognosis; reperfusion; vascular endothelium permeability

Our goals are; to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking leukocyte adhesion molecule receptors (CD11b, LFA-1), to investigate mechanisms by which blocking these receptors reduce ischemic cell damage, and to bring to fruition magnetic resonance imaging as a non-invasive method of assessing the response of ischemic tissue to a therapeutic intervention. To accomplish these goals we will employ experiments associated with three Specific Aims. Aim 1: The effect of anti-(CD11b, LFA-1) monoclonal antibodies on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage after transient MCA occlusion. Aim 2: Mechanisms by which the anti-CD11b and anti-LFA-1 reactive antibodies reduce ischemic cell damage will be investigated. 2(a); We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis; Infiltration of leukocytes, primarily neutrophils, into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. 2 (b). We will perform quantitative autoradiographic measurements of local cerebral blood flow at time points after transient MCA occlusion. Hypothesis; Neutrophils may contribute to ischemic cell damage in reperfusion injury by reducing local cerebral blood flow. 2(c): The permeability of the blood-brain barrier (BBB) will be evaluated at various times after transient MCA occlusion. Hypothesis; Neutrophils may contribute in part to ischemic cell damage by interacting with the capillary endothelium and thereby increasing the permeability of the BBB to water and neurotoxic substances. Aim 3: We will employ NMR methodology (Perfusion Imaging, Diffusion Weighted Imaging (DWI), T1 & T2 Imaging) to assess the physiological changes and efficacy of the anti- integrin therapeutic intervention. Hypothesis: With effective leukocyte anti-adhesion molecule therapy, the temporal profiles and values of the apparent diffusion constant of water (ADC)w) and CBF in the ischemic tissue will be modified, and the volume of the lesion as measured by T2 weighted imaging will be reduced compared to animals without antibody.

我们的目标是：减少大脑中动脉栓塞后缺血性细胞损伤， (MCA)通过选择性阻断白细胞粘附在大鼠闭塞 分子受体（CD 11b，LFA-1），以研究其机制， 阻断这些受体可以减少缺血性细胞损伤， 磁共振成像作为一种非侵入性的评估方法 缺血组织对治疗干预的反应。 到 为了实现这些目标，我们将采用与三个相关的实验， 具体目标。 目的1：抗（CD 11b，LFA-1）单克隆抗体对降低 将在经受短暂（2）的大鼠中研究缺血性细胞损伤 小时）MCA闭塞。 缺血性细胞损伤将被测量为一个函数， 抗体给药的剂量和时间。 假设：单克隆 与整联蛋白反应的抗体将减少缺血性细胞损伤， 作为抗体施用的剂量和时间的函数测量。 假设：与整联蛋白反应的单克隆抗体降低 短暂MCA闭塞后缺血细胞损伤。 目标2： 其中抗-CD 11b和抗-LFA-1反应性抗体减少缺血性 将研究细胞损伤。 2（a）;我们将测量和关联 中性粒细胞浸润到缺血性血管的程度的时间曲线 缺血性细胞损伤的组织。 假设：白细胞浸润， 主要是中性粒细胞进入缺血组织先于或伴随 与缺血性细胞损伤，并有助于缺血性细胞损伤后， 短暂性局灶性脑缺血 2（B）。 我们将进行定量分析 放射自显影测量的局部脑血流量在时间点 大脑中动脉短暂闭塞后 假设;中性粒细胞可能有助于 减少局部脑血流量对缺血再灌注损伤中细胞损伤作用 流 2（c）：血脑屏障（BBB）的渗透性将是 在短暂性MCA闭塞后的不同时间进行评价。 假设; 中性粒细胞可能通过相互作用而部分导致缺血性细胞损伤。 与毛细血管内皮细胞，从而增加渗透性 血脑屏障的水和神经毒性物质。 目标3：我们将使用NMR 方法学（灌注成像、扩散加权成像（DWI）、T1和T2 成像），以评估生理变化和抗- 整合素治疗干预。 假设：具有有效白细胞 抗粘附分子治疗的时间分布和价值， 缺血组织中水的表观扩散常数（ADC）w）和CBF 将被修改，并且通过T2加权测量的病变体积 与没有抗体的动物相比，成像将减少。