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Pathways of Alzehimer's amyloid assembly studied by computer simulations

通过计算机模拟研究阿尔茨海默淀粉样蛋白组装途径

基本信息

批准号：
7615674
负责人：
DMITRI Konstantinovich KLIMOV
金额：
$ 14.3万
依托单位：
GEORGE MASON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by investigator ): According to amyloid hypothesis the assembly of Abeta peptides into fibrils plays a central role in Alzheimer's disease. Recent experiments suggest that not only Abeta amyloid fibrils, but also Abeta oligomers are potent neurotoxic agents. However, due to complexity of amyloid assembly the associated molecular mechanisms remain poorly understood. The current proposal targets two distinct mechanisms of Alzheimer's amyloidogenesis - the formation of Abeta oligomers and the elongation of preexisting Abeta fibrils by deposition of individual peptides. The main questions of the project are how do these mechanisms of Alzheimer's amyloidogenesis manifest themselves on a single molecule level? Is it possible to develop a combined microscopic description of fibril growth and oligomer assembly, which together represent major events in Abeta amyloidogenesis? What is the molecular basis of anti-aggregation effect produced by certain non-steroidal anti-inflammatory drugs (NSAID)? To answer these questions a molecular model of the pathways of Abeta amyloid assembly will be developed. The proposed work relies on high-end parallel computing and multi-scale molecular modeling. To overcome computational challenges new protein model and new sampling algorithms are employed. Cross-validation strategies to reduce computational artifacts are incorporated in the research plan. The biomedical significance of the proposed work is that the knowledge of molecular mechanisms of Abeta aggregation can be used to devise strategies to control the levels of soluble and fibrillized Abeta peptides. In particular, the project findings will be useful in the design of new NSAID derivatives with stronger anti-aggregation propensity and Abeta imaging efficiency.

描述(由研究人员提供)：根据淀粉样蛋白假说，Abeta多肽组装成纤维在阿尔茨海默病中起着核心作用。最近的实验表明，不仅Aβ淀粉样蛋白纤维，而且Aβ寡聚体也是有效的神经毒剂。然而，由于淀粉样蛋白组装的复杂性，相关的分子机制仍然知之甚少。目前的建议针对阿尔茨海默氏症淀粉样变的两种不同机制--Aβ寡聚体的形成和通过个别肽的沉积延长先前存在的Aβ纤维。该项目的主要问题是阿尔茨海默氏症淀粉样变的这些机制是如何在单分子水平上表现出来的？是否有可能对纤维生长和寡聚体组装进行综合的微观描述，这两者共同代表了Abeta淀粉样变中的主要事件？某些非类固醇抗炎药(NSAID)产生抗聚集作用的分子基础是什么？为了回答这些问题，我们将建立Aβ淀粉样蛋白组装途径的分子模型。拟议的工作依赖于高端并行计算和多尺度分子建模。为了克服计算上的挑战，采用了新的蛋白质模型和新的采样算法。减少计算伪影的交叉验证策略被纳入研究计划。这项工作的生物医学意义在于，对Abeta聚集的分子机制的了解可以用来设计策略来控制可溶性和纤化的Abeta多肽的水平。特别是，该项目的发现将有助于设计具有更强的抗聚集倾向和Abeta成像效率的新的非甾体抗炎药衍生物。