BIOPHYSICS OF SICKLE CELL/ENDOTHELIAL CELL ADHERENCE

镰状细胞/内皮细胞粘附的生物物理学

• 批准号: 6183566
• 负责人: TIMOTHY M WICK
• 金额: $ 16.71万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-25 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183566
• 关键词: biophysics; cell adhesion; cell adhesion molecules; clinical research; erythrocytes; fibronectins; human subject; sickle cell anemia; thrombosis; thrombospondins; tissue /cell culture; vascular endothelium; von Willebrand factor

DESCRIPTION: The investigators propose to continue studies on the mechanisms of sickle cell adhesion to endothelial cells of the microvasculature, as further described by their abstract: "Polymerization of hemoglobin SS at low oxygen tension is assumed to be the dominant factor in sickle cell pathology. Since morphologic sickling is delayed after hemoglobin deoxygenation, factors which slow red cell microcirculatory transit are likely antecedents to microvascular occlusion, ischemic tissue damage, and pain episodes characteristic of sickle cell anemia. We hypothesize that sickle erythrocyte adherence to microvascular endothelium delays erythrocyte microcirculatory transit to initiate or propagate vaso-occlusion. Our studies have identified plasma factors, red cell receptors, and endothelial cell adhesion molecules which promote sickle cell adherence under flow. In vivo, adherence will have to occur under dynamic conditions and adhesion must be strong enough to withstand shear forces exerted by flowing blood to reperfuse occluded vessels and tissues. Thus, receptors, cell adhesion molecules, and adhesive proteins are necessary, but not sufficient for sickle cell adherence and vaso-occlusion. We hypothesize that in vivo, adherence biophysics (primarily strength) will regulate the extent of sickle cell adhesion and vaso-occlusion. Conditions which lead to extensive and strong adherence will be most relevant to the pathophysiology of sickle cell adherence and vaso-occlusion in vivo. To address this, experiments have been designed with the following specific aims: (1) Demonstrate that sickle cell adherence under flow is stronger than adherence under static conditions and that adherence under flow selects for cells expressing more adhesion receptors; (2) Quantify the strength of sickle-cell/endothelial adherence in response to red cell agonists, endothelial activators, and adhesive plasma proteins for cell populations and individual cells in the range of 0 - 10 dynes/cm2 shear stress. Particular emphasis will be placed on conditions which invoke multiple adherence pathways to mimic clinical conditions which may precipitate pain episodes in vivo, such as thrombosis or infection; (3) Develop flow channels with venular dimensions (20-50 micrometers) and demonstrate that sickle cell adherence in confined channels is strong. "Analysis of the biophysics of sickle cell adherence to endothelium under conditions which mimic those in the microcirculation will provide insights into the physiological conditions which promote extensive, rapid, and strong sickle cell/endothelial cell adherence likely leading to vaso-occlusive pain episodes. These studies will identify the most important parameters and adherence pathways to target for the development of therapeutic agents to inhibit or reverse adherence to ameliorate sickle cell pain episodes."

描述：研究人员建议继续研究 镰状细胞与内皮细胞的粘附机制 微脉管系统，如其摘要进一步描述： “血红蛋白 SS 在低氧张力下的聚合被认为是 镰状细胞病理学的主导因素。 由于形态镰状化是 血红蛋白脱氧延迟，减缓红细胞的因素 微循环转运可能是微血管闭塞的先兆， 缺血性组织损伤和镰状细胞病特有的疼痛发作 贫血。 我们假设镰状红细胞粘附在微血管上 内皮细胞延迟红细胞微循环转运以启动或 传播血管闭塞。 我们的研究已经确定了血浆因子，红色 细胞受体和促进镰状细胞形成的内皮细胞粘附分子 细胞在流动下贴壁。 在体内，粘附必须在以下条件下发生： 动态条件和附着力必须足够强以承受剪切力 流动的血液施加的力重新灌注闭塞的血管和组织。 因此，受体、细胞粘附分子和粘附蛋白是 对于镰状细胞粘附和血管闭塞来说是必要的，但还不够。 我们假设在体内，依从性生物物理学（主要是力量）将 调节镰状细胞粘附和血管闭塞的程度。 状况 导致广泛而强烈的遵守将与 体内镰状细胞粘附和血管闭塞的病理生理学。 到 为了解决这个问题，实验设计了以下具体内容 目的：（1）证明镰状细胞在流动下的粘附更强 比静态条件下的粘附性和流动条件下的粘附性选择 对于表达更多粘附受体的细胞； (2) 量化强度 镰状细胞/内皮细胞粘附响应红细胞激动剂， 内皮激活剂和细胞群的粘附血浆蛋白 单个细胞的剪切应力范围为 0 - 10 达因/平方厘米。 将特别强调调用多重条件的条件 模仿可能引发疼痛的临床状况的依从途径 体内事件，例如血栓形成或感染； （三）开拓流通渠道 具有小静脉尺寸（20-50 微米）并证明镰状细胞 受限渠道的遵守情况很强。 “镰状细胞粘附于内皮细胞的生物物理学分析 模仿微循环中的条件将提供见解 进入促进广泛、快速、有力的生理条件 镰状细胞/内皮细胞粘附可能导致血管闭塞性疼痛 剧集。 这些研究将确定最重要的参数和 治疗药物开发的靶标依从途径 抑制或逆转依从性以改善镰状细胞疼痛发作。”