Activation of cAMP-Mediated Sicke Cell Adhesion

激动剂诱导的信号转导是调节血小板、白细胞等细胞黏附的主要机制。然而，红细胞对激动剂的刺激通常被认为是惰性的；因此，激动剂在镰状红细胞中直接激活SS红细胞粘附性的信号相对较少。由于异常的SS RBC黏附被认为是导致镰状细胞患者遭受痛苦的血管闭塞危象的原因之一，因此了解调节这种黏附的机制是至关重要的。我们最近的一个重要发现是，SS红细胞对激动剂刺激非常敏感，导致与多种血管蛋白的黏附迅速而显著增加。在这里，我们建议扩展一下我们的 激动剂诱导cAMP的产生导致蛋白激酶A依赖的SS RBC粘附层粘连蛋白的激活。因此，肾上腺素和其他几种生理激动剂迅速增加了一部分患者的SS RBC粘附性，在导致这些激动剂升高的条件(如应激和疼痛)与血管闭塞之间提供了潜在的生理学联系。在这里，我们建议：1)建立肾上腺素反应性和无反应性镰状细胞患者红细胞的基础；2)鉴定参与肾上腺素诱导的SS红细胞黏附的受体亚型(S)，并识别诱导这一过程的其他自然发生的激动剂和激动剂受体；3)绘制介导刺激的SS红细胞与层粘连蛋白的AMP依赖的信号通路(S)；4)识别其他支持cAMP刺激的血管蛋白 5)cAMP刺激的SS红细胞黏附在体内系统中的作用。这些研究可能为破坏镰状细胞患者AMP介导的黏附相互作用带来新的治疗靶点。

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.