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.

羟基脲代表了镰状细胞病的新治疗方法