REACTIONS OF HYDROXYUREA WITH SICKLE CELL HEMOGLOBIN

描述：羟基脲代表了镰状细胞病的一种新的治疗方法， 每600名非洲裔美国人中就有1人患有这种疾病。而 羟基脲如何有益地影响镰状细胞病的分子机制 患者仍然未知，羟基脲与镰状细胞血红蛋白反应。的 长期目标是彻底和明确的建议研究 了解羟基脲与镰状细胞反应的贡献 血红蛋白提供了对镰状细胞的有益效果 接受羟基脲治疗的患者。这一目标是基于 假设1）羟基脲与镰状细胞血红蛋白反应 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一部分有益的结果， 镰状细胞病中的羟基脲疗法，3）一氧化氮（NO）或硝酰基 (HNO/NO '）的存在 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，和4）能够 产生镰状细胞S-亚硝基血红蛋白将证明有益的效果 类似于羟基脲。为了研究该反应，动力学和产物 羟基脲与氧、脱氧和甲硫氨酸反应的分布 将测定血红蛋白和镰状红细胞。硝酸的影响 还将确定镰刀形红细胞上的氧化物和硝酰基供体， 将开发一种新的水溶性硝酰基供体，并用镰刀进行评价。 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学性质， 红细胞将决定这些反应的后果。这些结果 将提供重要的信息，关于羟基脲的机制 在镰状细胞病中的作用， 应用上级治疗。

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.