Heterogeneous Nucleation in Sickle Cell Disease

镰状细胞病中的异质成核

• 批准号: 6775604
• 负责人: FRANK A FERRONE
• 金额: $ 22.05万
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6775604
• 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.

镰状细胞病的产生是由于经由双成核机制的聚合，所述双成核机制涉及溶液中的均质成核和镰状血红蛋白聚合物表面上的异相成核。 聚合物形成凝胶，最终导致毛细血管阻塞。 这项工作将继续测试在上一个资助期开发的异质成核的描述。 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。 我们将通过对修饰和突变血红蛋白的研究来测试我们的结构模型。 （由阿达奇博士和曼宁博士提供）总体目标是产生用于凝胶化动力学的结构上有动机的、计算上精确的模型。在上一个资助期的研究中，很明显，聚集体中分子的振动自由对聚合速率有着深刻的控制。 我们将测量几个突变体的成核率，这将影响振动熵。最后，我们将开始实验，使用粒子跟踪相关技术探测微流变学的凝胶作为域大小，聚合物质量和动力学形成的函数。 这将解决理解上的一个主要空白，即，良好描述的分子事件如何与形成的聚合物质量的刚性相关。 凝胶的刚性将与上面推导的振动熵进行比较。