PHYSIOLOGY OF MEMBRANE TRANSPORT IN NORMAL AND SICKLE CELL RED BLOOD CELLS

正常和镰状细胞红细胞膜运输的生理学

• 批准号: 6109616
• 负责人: Eugene P Orringer
• 金额: $ 11.39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6109616
• 关键词: antiport; biological transport; blood disorder chemotherapy; clinical trials; drug design /synthesis /production; drug screening /evaluation; erythrocyte count; erythrocyte membrane; erythrocytes; hemoglobin F; hemoglobin Ss; hemolysis; human subject; human therapy evaluation; hydroxyurea; longitudinal human study; polymerization; sickle cell anemia; sickle cell crisis; sickling inhibitor

Despite extensive investigation into its clinical and molecular pathophysiology, there still exists no treatment modality with proven efficacy for patients with sickle cell disease (SCD). However, based on a recently completed Phase I Trial, hydroxyurea (HU), a drug that increases hemoglobin F production, appears to show considerable promise as a prophylactic agent in SCD. Because HbF inhibits the polymerization of sickle hemoglobin (HbS), and since the polymerization process is the primary determinant of the hemolytic and vaso-occlusive severity of SCD, it has generally been assumed that the apparent clinical benefit of HU is linked to the increased circulating HbF levels. However, because HU has a variety of other effects on the sickle erythrocyte (SS RBC), it is our hypothesis that HU's efficacy in SCD is not simply a consequence of an increase in HbF production. Rather, we suggest that a number of the other RBC effects may also be important, and could well act synergistically with HbF, to inhibit HbS polymerization, to reduce the rate of hemolysis, and to ameliorate the course of the clinical illness. In this application, we have proposed to characterize a wide variety of physiological, rheological, and functional parameters of SS RBC before, and then longitudinally during the course of, HU therapy. Our goals are first to identify one or more baseline RBC parameters which might serve as predictors of a positive response to HU, both in terms of a decrease in the frequency of vaso-occlusive events and of a fall in the rate of red cell destruction. To date, no such predictor exists. Because of HU's toxicity and the unknown risks of its long-term administration in this patient population, a predictor would be quite valuable in SCD. We will also try to define the mechanism(s) by which HU exerts its clinical benefit by correlating and/or separating its HbF effect with/from its effects on other RBC parameters. These studies will employ both SS and AA RBC, the latter obtained from patients with one of the myeloproliferative disease. Finally, because HU is a potentially toxic drug with efficacy that remains to be proven, we will continue to examine alternative drugs or compounds that may also have a therapeutic role in SCD.

尽管对其临床和分子进行了广泛的研究 病理生理学，仍然没有经过验证的治疗方式 镰状细胞病（SCD）患者的功效。 但是，基于 最近完成的I期试验羟基脲（HU），一种药物 增加血红蛋白F产量，似乎表现出巨大的希望 作为SCD中的预防剂。 因为HBF抑制聚合 镰状血红蛋白（HBS），并且由于聚合过程是 SCD的溶血性和血管熟悉严重程度的主要决定因素， 通常认为HU的明显临床益处 与循环HBF水平升高有关。 但是，因为胡 对镰刀红细胞（SS RBC）有多种其他影响，这是 我们假设HU在SCD中的功效不仅仅是结果 HBF产生的增加。 相反，我们建议许多 其他RBC效应也可能很重要，并且可以采取行动 与HBF协同抑制HBS聚合，以减少 溶血率，并改善临床疾病的过程。 在此应用程序中，我们提出了各种各样的特征 SS RBC的生理，流变和功能参数， 然后在HU治疗过程中纵向。 我们的目标是 首先识别一个可能服务的基线RBC参数 作为对HU的积极反应的预测指标 在血管结构事件的频率和下降速度的频率下 红细胞破坏。 迄今为止，没有这样的预测因子。 由于 HU的毒性以及其长期管理的未知风险 该患者群体在SCD中将非常有价值。 我们 还将尝试定义HU发挥其临床的机制 通过将其HBF效应与/与其分开相关联，从中受益 对其他RBC参数的影响。 这些研究将同时采用SS和 AA RBC，后者是从患者中获得的 骨髓增生性疾病。 最后，因为胡是一种潜在的有毒 有疗效的药物尚待证明，我们将继续检查 替代药物或化合物在 scd。