Sickle Cell Adhesion

镰状细胞粘附

• 批准号: 6887394
• 负责人: DHANANJAY K. KAUL
• 金额: $ 23.16万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887394
• 关键词: CD47 molecule; blood vessel occlusion; cell adhesion; cooperative study; disease /disorder model; erythrocytes; flow cytometry; genetically modified animals; human data; hydroxyurea; integrins; intermolecular interaction; laboratory mouse; laminin; ligands; microarray technology; nitric oxide; nonhuman therapy evaluation; receptor; selectins; sickle cell anemia; vascular endothelium; von Willebrand factor

We propose that abnormal interaction of sickle (SS) cells with vascular endothelium is the initiating event leading to the development of vascular occlusion in sickle cell anemia. This is because increased SS cell adhesion is expected to result in delayed microvascular transit times, dense cell trapping, enhanced red cell sickling and vase-occlusion. We posit that SS cell adhesion is multifactorial in nature, involving a host of modulating factors and receptor-ligand interactions. In the proposed studies, we will examine the "multifactorial nature" of SS cell adhesion, and explore its role in vascular occlusion in vivo. This proposal will focus on specific ligand-receptor interactions, emphasizing the role of endothelial activation/damage and red cell heterogeneity in SS cell adhesion. To this end, we will use state-of-the-art transgenic-knockout sickle mouse models and relevant ex vivo assay systems, and explore therapeutic approaches that would interfere with this pathologic interaction. Using intravital techniques and an integrated physiological approach, we will test the following: 1. Test the hypothesis that endothelial activation and damage is accompanied by expression of specific adhesion molecules that modulate SS cell adhesion to endothelium in vivo. To test this hypothesis we will investigate the role of adhesion molecules whose expression is potentially affected by endothelial activation and damage. We will evaluate the role of endothelial von Willebrand factor (vWf), P-selectin, laminin (a matrix protein) and endothelial alphaVbeta3 integrin (a receptor to several adhesive proteins); 2. Test the hypothesis that sickle cell density classes are characterized by heterogenous distribution of adhesion receptors affecting their propensity to adhesion. To test this hypothesis, we will investigate sickle mouse red cell density populations (reficulocytcs and dense cells) for certain adhesion receptors and evaluate their role in adhesion, with emphasis on the role of integrin-associated protein (IAP or CD47); 3. Test the hypothesis that NO will modulate red cell adhesion in vivo. We will test this hypothesis by: i) Investigation of the effect of NO promoting agents (e.g., L-arginine supplementation); ii) Evaluation of the effect of NO inhibition; iii) anti-oxidant therapy; iv) hydroxyurea therapy. Thus, we expect to identify now therapeutic approaches to alleviate adhesion-induced flow abnormalities and vaso-occlusion in sickle cell disease.

我们认为，镰状细胞（SS）与血管内皮的异常相互作用是导致镰状细胞贫血中血管闭塞的起始事件。这是因为预计SS细胞粘附的增加会导致微血管迁移时间延迟，密集的细胞捕获，增强的红细胞疾病和花瓶 - 渗入。我们认为SS细胞粘附本质上是多因素的，涉及许多调节因素和受体配体相互作用。在拟议的研究中，我们将检查SS细胞的“多因素性质” 粘附并探索其在体内血管闭塞中的作用。该建议将集中于特定的配体 - 受体相互作用，强调内皮激活/损伤和红细胞异质性在SS细胞粘附中的作用。为此，我们将使用最先进的转基因敲除小鼠模型和相关的离体测定系统，并探索会干扰这种病理相互作用的治疗方法。使用插入性技术和综合生理方法，我们将测试以下内容：1。测试一个假设，即内皮激活和损伤伴随着调节SS细胞粘附对体内内皮的特定粘附分子的表达。为了检验这一假设，我们将研究粘附分子的作用，其表达可能会受到内皮激活和损伤的影响。我们将评估内皮von Willebrand因子（VWF），P-选择蛋白，层粘连蛋白（基质蛋白）和内皮alphavbeta3整合素（几种粘合剂蛋白的受体）的作用； 2。检验的假设，即镰状细胞密度类别的特征是粘附受体的异质分布影响其粘附倾向。为了检验这一假设，我们将研究某些粘附受体的镰状小鼠红细胞密度群（Reficulocytcs和致密细胞），并评估其在粘附中的作用，重点是整联蛋白相关蛋白（IAP或CD47）的作用； 3。检验假设，即NO将在体内调节红细胞粘附。我们将通过：i）对无促进剂的影响进行研究（例如，补充l-精氨酸）； ii）评估NO抑制作用的影响； iii）抗氧化治疗； iv）羟基脲治疗。因此，我们希望现在确定 减轻镰状细胞疾病中粘附诱导的流动异常和血管结合的治疗方法。