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: 6390252
• 负责人: S BRUCE King
• 金额: $ 20.65万
• 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 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390252
• 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：羟基脲代表了镰状细胞病的一种新治疗方法， 这种疾病影响了六百分之一的非洲裔美国人。虽然 羟基脲如何有益地影响镰状细胞病的分子机制 患者仍不清楚，羟基脲会与镰状细胞血红蛋白发生反应。这 拟议研究的长期目标是彻底、清晰地 了解羟基脲和镰状细胞反应的贡献 血红蛋白提供了镰状细胞观察到的有益效果 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）镰状细胞的形成 S-亚硝基血红蛋白贡献了部分有益结果 羟基脲治疗镰状细胞病，3) 一氧化氮 (NO) 或硝酰基 羟基脲与镰状细胞反应过程中产生的（HNO/NO'） 血红蛋白代表镰状细胞亚硝基的最终来源 S-亚硝基血红蛋白，以及 4) 一氧化氮或硝酰基供体 产生镰状细胞 S-亚硝基血红蛋白将显示出有益的效果 与羟基脲类似。为了研究该反应的动力学和产物 羟基脲与氧、脱氧和met镰状细胞反应的分布 将测定血红蛋白和镰状红细胞。硝酸盐的影响 镰状红细胞上的氧化物和硝酰基供体也将被确定 将开发一种新的水溶性硝酰基供体并用镰刀进行评估 红细胞。关于延迟时间和百分比的生物物理测量 镰状血红蛋白和纯化血红蛋白的流变特性和 红细胞将决定这些反应的后果。这些结果 将提供有关羟基脲机制的重要信息 在镰状细胞病中的作用对于设计和治疗具有重要意义 优越的治疗方法的应用。