Heterogenous Nucleation in Sickle Cell Disease

镰状细胞病中的异质成核

基本信息

批准号：
7802868
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
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-12-20 至 2012-03-31
项目状态：
已结题

项目摘要

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.

该赠款应用的重点是如何结合有关的广泛基本知识的问题镰状血红蛋白聚合成理性的治疗方法。 1。我们将完成混合物对均质和异源成核的影响的描述 HBS，并使用激光光解方法测试描述。这对于预测基因疗法和药物疗法的结局，并将为理解混合物奠定基础配体和非配体HBS。 2。作为一种治疗方法，我们将扩展双核模型，以包括液态液相 - 过渡及其对聚合物形成的影响。由于拥挤的巨大影响（我们先前测量的），密集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的治疗潜力提高了十倍的改善血红蛋白，这是当前羟基尿素疗法的基础。效果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合并。 3。我们将继续测量纤维的柔韧性和域刚度在上一个赠款期开始，（a）我们正在通过磁驱动的珠子和同时光学测量聚合物结构域的刚度想象生长域（b）我们正在使用图案化光解测量纤维刚性以创建弯曲的光通道可以通过，纤维可以生长。许多蛋白质关联疾病是已知的，尽管没有一个像HB的疾病那样很好。结果，关于生物物理机制的问题的类型通常是首先为HB饲养，然后他们的解决方案也可以研究其他疾病。因此，预计此处产生的成功将对其他蛋白质关联问题具有有用的衍生作用。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metastable gels: A novel application of Ogston theory to sickle hemoglobin polymers.

亚稳态凝胶：奥格斯顿理论在镰状血红蛋白聚合物中的新应用。

DOI：
10.1016/j.bpc.2011.01.007
发表时间：
2011
期刊：
Biophysical chemistry
影响因子：
3.8
作者：
Weng,Weijun;Ferrone,FrankA
通讯作者：
Ferrone,FrankA

Universal metastability of sickle hemoglobin polymerization.

镰状血红蛋白聚合的普遍亚稳定性。

DOI：
10.1016/j.jmb.2008.01.083
发表时间：
2008
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Weng,Weijun;Aprelev,Alexey;Briehl,RobinW;Ferrone,FrankA
通讯作者：
Ferrone,FrankA

Flexibility and nucleation in sickle hemoglobin.

镰状血红蛋白的灵活性和成核。

DOI：
10.1006/jmbi.2001.5163
发表时间：
2001
期刊：
Journal of molecular biology.
影响因子：
0
作者：
Ivanova,M;Jasuja,R;Krasnosselskaia,L;Josephs,R;Wang,Z;Ding,M;Horiuchi,K;Adachi,K;Ferrone,FA
通讯作者：
Ferrone,FA

Calibrating Sickle Cell Disease.

校准镰状细胞病。