MECHANISM AND KINETICS OF SICKLE CELL HEMOGLOBIN

镰状细胞病的特征是突变的聚合体。 低氧条件下增加红血球的血红蛋白形态 细胞僵硬导致微血管闭塞。这场战争的严重性 疾病很可能部分地依赖于 低氧条件下的聚合反应及其动力学 肺部复氧时解聚(融化)。虽然 聚合反应的机理和动力学已经得到了广泛的研究 在研究中，更少的工作集中在聚合物熔融上。焦点 本研究的目的是阐明镰状细胞的机制和动力学。 血红蛋白聚合物熔化。我们会特别注意 研究配体(氧或一氧化碳)结合的作用 熔化过程中聚合物中的血红蛋白分子。其他因素 可能会影响熔融动力学，如聚合物的长度将 以及聚合物熔融动力学和变化之间的联系 镰状细胞形状和变形性。这项研究不仅是 对于理解聚合反应的物理和 解聚，也与了解镰状细胞疾病有关 从而为一种新的治疗形式提供了可能性。 拟议的工作将通过一种新颖的组合来完成 光谱技术。一种特殊的仪器，能够 同时进行吸收光谱测量，线性 二向色性、圆二向色性、圆偏振发光以及 偏振光散射是为应用于这一领域而建立的 项目。光谱测量将通过以下方式完成 毫秒的分辨率，所以镰状细胞聚合物的数量， 聚合物和溶液相分子的连接状态，以及 四种状态的血红蛋白分子可以同时 被确定为聚合物熔融被诱导。这些产品的使用 该项目中的光谱技术(以及它们的组合)可能 从而在其他研究中得到应用。我们会特别注意 在评估偏振光散射时(先前显示为 对聚合物浓度极其敏感)作为生物物理工具。 提供这种能力的新技术 独特的测量组合确保了 新现象的发现。

Sickle cell disease is characterized by the polymerization of a mutant form of hemoglobin under hypoxic conditions which increases red blood cell rigidity leading to microvascular occlusion. The severity of the disease is most likely partially dependent on the kinetics of polymerization during hypoxic conditions and on the kinetics of depolymerization (melting) upon reoxygenation at the lungs. Although the mechanism and kinetics of polymerization have been extensively studied, much less work has concentrated on polymer melting. The focus of this study is to elucidate the mechanism and kinetics of sickle cell hemoglobin polymer melting. Special attention will be put on investigating the role of ligand (oxygen or carbon monoxide) binding to hemoglobin molecules in the polymer during melting. Other factors that may affect melting kinetics such as the length of the polymers will be studied as well as the link between polymer melting kinetics and changes in sickle cell shape and deformability. This study is not only important in regard to understanding the physics of polymerization and depolymerization but also in regard to understanding sickle cell disease thereby providing potential for a new form of treatment. The proposed work will be accomplished by a novel combination of spectroscopic techniques. A special instrument capable of simultaneously conducting spectral measurements of absorption, linear dichroism, circular dichroism, circularly polarized luminescence, and polarized light scattering is being built for application to this project. The spectral measurements will be accomplished with millisecond resolution so that the amount of sickle cell polymer, the ligation state of the polymer and solution phase molecules, and the quaternary state of the hemoglobin molecules can be simultaneously determined as polymer melting is induced. The use of these spectroscopic techniques (and their combination) in this project could lead to applications in other studies. Special attention will be paid in evaluating polarized light scattering (previously shown to be extremely sensitive to polymer concentration) as a biophysical tool. The novel technology that is providing the ability to perform this unique combination of measurements ensures the potential of the discovery of new phenomena.