Activation of Sickle Red Cell Adhesion

镰状红细胞粘附的激活

• 批准号: 6676784
• 负责人: Rahima Zennadi
• 金额: $ 11.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6676784
• 关键词: cell adhesion; clinical research; sickle cell anemia

DESCRIPTION (provided by applicant): The vaso-occlusive process in patients with sickle cell disease (SCD) is complex and involves interactions both between hemoglobin S red blood cells (SS RBC) and vascular endothelium, and between SS RBC and leukocytes adherent to endothelium. Vaso-occlusive events lead to recurrent pain and cerebrovascular accidents in both children and adults, as well as other types of end-organ damage, including pulmonary hypertension and renal failure. However, the physiologic triggers inducing SS RBC adhesion and vaso-occlusion are poorly understood, and elucidation of these mechanisms at the molecular level would allow development of new preventive and treatment strategies to abrogate vaso-occlusive events. We have begun to explore the role of SS RBC cAMP signal transduction pathways in upregulating SS RBC adhesion to endothelial cells (EC). We have found that treatment of SS RBC with agents such as epinephrine, that lead to elevation of intracellular cAMP, induced enhanced SS RBC adhesion to EC and that this signaling pathway is also dependent on tyrosine phosphorylation. We have also shown that interaction between SS RBC and EC is mediated at least primarily by the adhesion receptor LW (ICAM-4) on SS RBC, which binds to alphav-beta3 integrin on EC. LW also binds to leukocyte integrins. We therefore hypothesize that abnormal circulating SS RBC adhesion to endothelium and to adherent leukocytes may at least in part be due to SS RBC adhesion receptor activation in vivo by processes involving upregulation of endogenous cAMP, leading to activation of LW adhesion receptor on SS RBC. We propose therefore to explore the molecular basis of SS RBC adhesion to both endothelium and leukocytes. Our specific aims are 1) to characterize the effects of physiologic adrenergic agonists known to lead to increased cAMP on LW-mediated SS RBC adhesion to endothelial cells both in vitro and ex vivo; 2) to characterize the mechanism of activation of the LW receptor; and 3) to investigate the possible role of LW in the interaction of SS RBC with leukocytes. Overall, these experiments will elucidate the molecular mechanisms of LW-mediated SS RBC adhesion to endothelium and leukocytes, and thus how physiologic stress and stress hormones may contribute to vaso-occlusion.

描述（由申请人提供）： 镰状细胞疾病（SCD）患者的血管熟悉过程很复杂，涉及血红蛋白的红细胞（SS RBC）和血管内皮之间的相互作用，SS RBC和白细胞之间遵循内皮的ss RBC和白细胞之间的相互作用。血管熟悉的事件导致儿童和成人的复发性疼痛和脑血管事故，以及其他类型的最终器官损伤，包括肺动脉高压和肾衰竭。然而，诱导SS RBC粘附和血管结合的生理触发因素知之甚少，并且在分子水平上阐明这些机制将允许制定新的预防和治疗策略来消除血管核酸的事件。我们已经开始探讨SS RBC CAMP信号转导途径在上调SS RBC对内皮细胞（EC）的作用。我们发现，用肾上腺素等药物（导致细胞内cAMP升高）对SS RBC进行处理，诱导了SS RBC对EC的增强，并且该信号传导途径也取决于酪氨酸磷酸化。我们还表明，SS RBC和EC之间的相互作用至少主要是由SS RBC上的粘附受体LW（ICAM-4）介导的，该粘附受体LW（ICAM-4）在EC上与Alphav-Beta3整合素结合。 LW还与白细胞整合素结合。因此，我们假设循环SS RBC对内皮和粘附的白细胞的异常至少可能部分是由于SS RBC粘附受体受体在体内通过涉及内源性营地上调的过程在体内激活，从而导致LW粘附受体在SS RBC上的激活。因此，我们建议探索SS RBC粘附于内皮和白细胞的分子基础。我们的具体目的是1）表征生理性肾上腺素能激动剂的影响，已知导致在LW介导的SS RBC粘附上增加cAMP对体外和Ex Vivo的内皮细胞的cAMP增加； 2）表征LW受体激活的机理； 3）研究LW在SS RBC与白细胞相互作用中的可能作用。总体而言，这些实验将阐明LW介导的SS RBC粘附对内皮和白细胞的分子机制，从而生理应力和应激激素如何有助于血管折叠。