Heterogenous Nucleation in Sickle Cell Disease

镰状细胞病中的异质成核

• 批准号: 7589826
• 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/7589826
• 关键词: Address; Applications Grants; Crowding; 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; Polymers; Progress Reports; Property; Proteins; Sickle Cell Anemia; Sickle Hemoglobin; Solutions; Techniques; Temperature; Testing; Theoretical model; Therapeutic; Work; base; flexibility; gene therapy; mutant; novel; numb protein; photolysis; polymerization; success

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 hydroxyureatherapy. 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 so 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.

这一资助申请的重点是如何将广泛的基础知识， 镰状血红蛋白聚合成合理的治疗方法。 1.我们将完成混合物对均匀和非均匀成核作用的描述 的HbS，并使用激光光解方法测试描述。这将是关键的预测 结果基因疗法和药物疗法，并将奠定基础，了解混合物 配体和非配体的HbS。 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- 转变及其对聚合物形成的影响。由于拥挤的戏剧性影响（我们 在其他区域（如先前测量的），致密液体区域的形成降低了其他区域的Hb浓度。 这种方法提供了多达10倍的改善比诱导胎儿的治疗潜力， 血红蛋白，这是目前羟基脲疗法的基础。这种影响已经在 我们的初步工作。光解测试还将确定成核和相分离是否正确 加起来 3.我们将继续在上一个资助期开始的纤维柔韧性和畴刚性的测量， 正在测量刚性的聚合物域的磁力驱动珠和同时光学 （B）我们使用图案化的光解来测量纤维刚性， 弯曲的光学通道，光纤可以通过这些通道生长。 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往往是 他们首先提出了HbS，然后他们的解决方案也可用于研究其他疾病。因此，我们认为， 这里产生的成功预期对其他蛋白质缔合问题具有有用的副产品。