Activation of cAMP-Mediated Sicke Cell Adhesion

cAMP 介导的病细胞粘附的激活

• 批准号: 7407406
• 负责人: Leslie V. Parise
• 金额: $ 41.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407406
• 关键词: A kinase anchoring protein; Adenylate Cyclase; Adhesions; Adhesiveness; Adhesives; Adrenergic Receptor; Age; Agonist; Blood Vessels; Cell Adhesion; Cell Line; Cells; Characteristics; Condition; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease; Disruption; Endothelial Cells; Epinephrine; Exhibits; Human; Laboratories; Laminin; Lead; Leukocytes; Link; Maps; Mediating; Mediator of activation protein; Pain; Pathway interactions; Patients; Physiological; Platelet Adhesiveness; Positioning Attribute; Process; Production; Protein Isoforms; Proteins; Rat Protein; Rattus; Recurrence; Role; Sickle Cell; Signal Pathway; Signal Transduction; Site; Staging; Stress; System; Testing; Therapeutic Intervention; adhesion receptor; base; design; in vivo; novel therapeutics; receptor; sickling; therapeutic target

Agonist-induced signaling is a primary mechanism regulating adhesiveness of platelets, leukocytes and other cells. However, RBCs are generally considered to be inert to agonist stimulation; thus signaling in sickle (SS) RBCs by agonists to directly activate SS RBC adhesiveness is relatively unexplored. Because abnormal SS RBC adhesion is believed to contribute to the painful vaso-occlusive crises suffered by sickle cell patients, it is crucial to understand mechanisms that modulate this adhesion. We recently made the important finding that SS RBCs are very responsive to agonist stimulation, resulting in a rapid and pronounced increase in adhesion to multiple vascular proteins. Here we propose to expand upon our findings that agonist-induced cAMP production results in a protein kinase A-dependent activation of SS RBC adhesion to laminin. Thus, epinephrine and several other physiologic agonists rapidly increase SS RBC adhesion in a subset of patients, providing a potential physiologic link between conditions that elevate these agonists, such as stress and pain, with vaso-occlusion. Here we propose to: 1) establish the basis for epinephrine-responsive and non-responsive sickle cell patient RBCs, 2) identify the receptor subtype(s) involved in epinephrine-induced SS RBC adhesion and identify additional naturally occurring agonists and agonist receptors that induce this process, 3) map the AMP-dependent signaling pathway(s) mediating stimulated SS RBC adhesion to laminin, 4) identify additional vascular proteins that support cAMP-stimulated SS RBC adhesion and the receptors/sites mediating these adhesive interactions, and 5) determine the role of cAMP-stimulated SS RBC adhesion in an in vivo system. These studies are likely to lead to new therapeutic targets for the disruption of AMP-mediated adhesive interactions in sickle cell patients.

激动剂诱导的信号传导是调节血小板、白细胞和其他细胞粘附性的主要机制。然而，红细胞通常被认为对激动剂刺激是惰性的；因此，镰状红细胞（SS）中的信号通过激动剂直接激活SS红细胞粘附性的研究相对较少。因为异常SS红细胞粘连被认为是镰状细胞患者痛苦的血管闭塞危机的原因之一，因此了解调节这种粘连的机制至关重要。我们最近取得了重要的发现，SS红细胞对激动剂刺激非常敏感，导致对多种血管蛋白的粘附迅速而显著地增加。在此，我们建议扩大我们的