Heterogenous Nucleation in Sickle Cell Disease

镰状细胞病中的异质成核

• 批准号: 7198089
• 负责人: FRANK A FERRONE
• 金额: $ 25.49万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198089
• 关键词: Address; Applications Grants; Crowding; Decompression Sickness; Dependence; Disease; Disease Association; Entropy; Fetal Hemoglobin; Fiber; Foundations; Grant; Hemoglobin; Knowledge; Lasers; Ligands; Liquid substance; Measurement; Measures; Mechanics; Methods; Modeling; Modification; Molecular; Muscle Rigidity; Optics; Outcome; Pattern; Pharmacotherapy; Phase; Phase Transition; Phosphate Buffer; Physiological; Pliability; Polymers; Progress Reports; Property; Proteins; Rate; Sickle Cell Anemia; Sickle Hemoglobin; Solutions; Techniques; Temperature; Testing; Theoretical model; Therapeutic; Work; base; gene therapy; hydroxyurea; mutant; novel; numb protein; photolysis; polymerization; success

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（由申请人提供）：该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.我们将完成的混合物对均匀和异质成核的HbS的影响的描述，并使用激光光解方法测试的描述。这对于预测基因治疗和药物治疗的结果至关重要，并将为理解配体和非配体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，包括液-液相变及其对聚合物形成的影响。由于拥挤的巨大影响（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10倍，这是目前羟基脲治疗的基础。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.我们将继续测量纤维的柔韧性和域的刚性开始在最后一个授权期间，（a）我们正在测量的刚性聚合物域的磁驱动珠和同时光学成像的增长域（B）我们正在测量纤维刚性使用图案化的光解，以创建弯曲的光学通道，通过光纤可以生长。许多蛋白质相关疾病是已知的，尽管没有一个像HbS那样被很好地表征。因此，可以提出的关于生物物理机制的问题类型通常首先针对HbS提出，然后它们的解决方案也可用于研究其他疾病。因此，这里产生的成功预计将有有用的副产品，以其他蛋白质的关联问题。