Heterogeneous Nucleation in Sickle Cell Disease

镰状细胞病中的异质成核

• 批准号: 6537291
• 负责人: FRANK A FERRONE
• 金额: $ 22.08万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-20 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537291
• 关键词: biophysics; capillary; erythrocytes; fluid flow; gel; hemoglobin F; hemoglobin Ss; physical model; polymerization; polymers; protein structure function; sickle cell anemia; thermodynamics; viscosity

Sickle cell disease arises because of polymerization via a double nucleation mechanism involving homogeneous nucleation in solution and heterogeneous nucleation onto sickle hemoglobin polymer surfaces. The polymers form a gel that ultimately leads to capillary occlusion. This work will continue testing the description of heterogeneous nucleation developed in the last grant period. Nucleation rates on HbF mixtures with HbS will be measured and compared with the improved theories we have now developed. We will test our structural model by studies on modified and mutant hemoglobins. (provided by Dr. Adachi and Dr. Manning) The Overall aim is to produce a structurally motivated, computationally accurate model for gelation kinetics. In the studies in the last grant period it has become apparent that vibrational freedom of molecules within the aggregate expert profound control over the rate of polymerization. We will measure nucleation rates for several mutants, which are expected to affect the vibrational entropy. Finally we will begin experiments using particle-tracking- correlation techniques to probe the microrheology of gels as a function of domain size, polymer mass, and kinetics of formation. This will address a major gap in understanding, viz. how the well-described molecular events relate to the rigidity of the polymer mass formed. Rigidity of the gels will be compared with the vibrational entropy deduced above.

镰状细胞病的发生是由于聚合通过双重成核机制，包括溶液中的均匀成核和镰状血红蛋白聚合物表面的不均匀成核。聚合物形成凝胶，最终导致毛细血管闭塞。这项工作将继续测试在上一个资助期间开发的非均相成核描述。将测量HbF与HbS混合物的成核速率，并与我们现在开发的改进理论进行比较。我们将通过对改良和突变血红蛋白的研究来测试我们的结构模型。（由Dr. Adachi和Dr. Manning提供）总体目标是产生一个结构动机，计算精确的凝胶动力学模型。在上一个资助期的研究中，很明显，聚合体内分子的振动自由度对聚合速度具有深远的控制作用。我们将测量几种突变体的成核速率，这将影响振动熵。最后，我们将开始实验，使用颗粒跟踪相关技术来探测凝胶的微流变学，作为畴大小，聚合物质量和形成动力学的函数。这将解决理解上的一个主要差距，即描述良好的分子事件如何与形成的聚合物质量的刚性相关。将凝胶的刚度与上述推导的振动熵进行比较。