REACTIONS OF HYDROXYUREA WITH SICKLE CELL HEMOGLOBIN

羟基脲与镰状细胞血红蛋白的反应

• 批准号: 6527565
• 负责人: S BRUCE King
• 金额: $ 24.08万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-10 至 2003-12-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527565
• 关键词: clinical research; drug interactions; hemoglobin Ss; human tissue; hydroxyurea; nitric oxide; nitroso compounds

DESCRIPTION: Hydroxyurea represents anew treatment for sickle cell disease, a condition that affects 1 in 600 Americans of African descent. While the molecular mechanisms of how hydroxyurea beneficially affect sickle cell disease patients remain unknown, hydroxyurea reacts with sickle cell hemoglobin. The long-- term goal of the proposed research is to thoroughly and clearly understand the contribution the reaction of hydroxyurea and sickle cell hemoglobin provides towards the beneficial effects observed with sickle cell disease patients undergoing hydroxyurea therapy. This goal is based upon the hypotheses that 1) the reaction of hydroxyurea with sickle cell hemoglobin forms sickle cell S-nitroso hemoglobin, 2) the formation of sickle cell S-nitroso hemoglobin contributes a portion of the beneficial consequences of hydroxyurea therapy in sickle cell disease, 3) nitric oxide (NO) or nitroxyl (HNO/NO') produced during the reaction of hydroxyurea and sickle cell hemoglobin represent the ultimate source of the nitroso group of sickle cell S-nitroso hemoglobin, and 4) nitric oxide or nitroxyl donors capable of producing sickle cell S-nitroso hemoglobin will demonstrate beneficial effects similar to hydroxyurea. To study this reaction, the kinetics and product distribution of the reaction of hydroxyurea and oxy, deoxy, and met sickle cell hemoglobin and sickle red blood cells will be determined. The effects of nitric oxide and nitroxyl donors on sickle red blood cells will also be determined and a new water-soluble nitroxyl donor will be developed and evaluated with sickle red blood cells. Biophysical measurements regarding the delay time and percent sickle hemoglobin and the rheological properties of purified hemoglobins and red cells will determine the consequences of these reactions. These results will provide important information regarding the mechanism of hydroxyurea action in sickle cell disease that would be significant in the design and application of superior treatments.

描述：羟基脲是治疗镰状细胞病的新方法。 每600名非洲裔美国人中就有1人受到影响。而当 羟基脲有益影响镰状细胞病的分子机制 患者仍不清楚，羟基尿素与镰状细胞血红蛋白发生反应。这个 拟议研究的长期目标是彻底和清楚地 了解羟基脲与镰状细胞反应的贡献 血红蛋白对观察到的镰状细胞的有益作用 接受羟基脲治疗的疾病患者。这一目标是基于 假设1)羟基脲与镰状细胞血红蛋白的反应 形成镰状细胞S-亚硝基血红蛋白，2)形成镰状细胞 S-亚硝基血红蛋白贡献了部分有益后果 羟基脲治疗镰状细胞病，3)一氧化氮(NO)或氮氧化物 (HNO/NO‘)在羟基脲与镰状细胞反应中产生 血红蛋白是镰状细胞亚硝基的最终来源 S-亚硝基血红蛋白，以及4)一氧化氮或氮氧供体 生产镰状细胞S亚硝基血红蛋白将显示出有益的效果 类似于羟基脲。为了研究这一反应，动力学和产物 羟基脲与氧、脱氧和甲硫氨酸镰状细胞反应的分布 将测定血红蛋白和镰刀状红细胞。硝酸盐的影响 还将测定镰刀状红细胞上的氧化物和氮氧基供体，并 一种新的水溶性氮氧基供体将被开发并用镰刀进行评估 红血球。关于延迟时间和百分比的生物物理测量 镰刀状血红蛋白和纯化的血红蛋白的流变性 红细胞将决定这些反应的后果。这些结果 将提供有关羟基脲作用机理的重要信息 在镰状细胞疾病中的作用将在设计和 应用优越的治疗方法。