Heterogenous Nucleation in Sickle Cell Disease

镰状细胞病中的异质成核

• 批准号: 7094810
• 负责人: FRANK A FERRONE
• 金额: $ 26.25万
• 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 2011-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094810
• 关键词: biomechanics; biophysics; clinical research; fluid; hemoglobin As; hemoglobin F; hemoglobin Ss; human subject; magnetic field; model design /development; molecular /cellular imaging; mutant; phase change; photolysis; physical model; polymerization; polymers; protein structure function; sickle cell anemia; thermodynamics

DESCRIPTION (provided by applicant): This grant application is focused on the question of how to incorporate the extensive basic knowledge of sickle hemoglobin polymerization into rational therapeutic approaches. 1. We will complete the description of the effect of mixtures on homogeneous and heterogenous nucleation of HbS, and test the description using laser photolysis methods. This will be critical for prediction of the outcome both of gene therapies and drug therapies, and will lay the groundwork for understanding mixtures of liganded and unliganded HbS. 2. As an approach to therapy, we will extend the double nucleation model to include liquid-liquid phase- transitions and their effect on polymer formation. Because of the dramatic effects of crowding (which we have previously measured), the formation of dense liquid regions lowers the Hb concentration elsewhere. This approach offers as much as a tenfold improvement over the therapeutic potential of inducing Fetal hemoglobin, which is the foundation of present hydroxyurea therapy. The effect has already been seen in our preliminary work. Photolysis tests will also determine if nucleation and phase separation are correctly combined. 3. We will continue measurements of fiber flexibility and domain rigidity begun in the last grant period, (a) We are measuring the rigidity of polymer domains by magnetically driven beads and simultaneous optical imagining of the growing domains (b) We are measuring fiber rigidty using patterned photolysis to create bent optical channels through which fibers can grow. A number of protein association diseases are known, though none are as well characterized as that of HbS. As a result, the types of questions that can be raised about the biophysical mechanism have often been raised first for HbS, and their solutions then become available to study other diseases as well. Hence, successes generated here are expected to have useful spin-offs to other protein association problems.

描述(由申请者提供)：这项资助申请的重点是如何将镰状血红蛋白聚合的广泛基础知识纳入合理的治疗方法。1.我们将完成混合物对HBS均相成核和非均相成核影响的描述，并使用激光光解方法对描述进行检验。这将对预测基因疗法和药物疗法的结果至关重要，并将为理解配基和非配基HBs的混合物奠定基础。2.作为一种治疗方法，我们将扩展双成核模型，以包括液-液相变及其对聚合物形成的影响。由于拥挤的戏剧性影响(我们之前已经测量过)，稠密液体区域的形成降低了其他地方的Hb浓度。这种方法比诱导胎儿血红蛋白的治疗潜力提高了十倍之多，这是目前羟基尿素疗法的基础。在我们的前期工作中已经看到了效果。光解测试还将确定成核和相分离是否正确结合。3.我们将继续测量从上一个授权期开始的纤维柔韧性和微区硬度，(A)我们正在通过磁珠和同时对不断增长的微区进行光学成像来测量聚合物微区的硬度(B)我们正在使用图案化的光解来测量纤维的硬度，以创建弯曲的光学通道，光纤可以通过该通道生长。许多蛋白质相关性疾病是已知的，尽管没有一种疾病像HBS那样具有良好的特征。因此，可以提出的关于生物物理机制的问题类型往往首先被提出给哈佛商学院，然后他们的解决方案也可以用于研究其他疾病。因此，这里产生的成功有望对其他蛋白质关联问题产生有益的副产品。