International Research Fellowship Program: Solid-State NMR Studies of Amyloid Fibrils

国际研究奖学金计划使美国科学家和工程师能够在国外进行三到二十四个月的研究。该计划的奖项提供了联合研究的机会，并利用国外独特或互补的设施、专业知识和实验条件。该奖项将支持Jeremy C.Flinders博士与德国柏林分子药理研究所Hartmut Oschkinat博士合作的为期22个月的研究奖学金。淀粉样纤维是与许多严重疾病有关的错误折叠的蛋白质聚集体，包括普恩和阿尔茨海默病、II型糖尿病和亨廷顿病。这些纤维的确切形成机制目前还不清楚，主要是因为缺乏足够的原子级结构信息。这种错误折叠形成的结构传统上很难研究，因为它们包含不溶于水且不结晶的细长细丝。然而，它们适合于使用最近的固态核磁共振(核磁共振)技术进行研究。这一研究项目的重点是确定一个模型淀粉样蛋白系统的高分辨率结构，并使用这些信息来研究纤维的形成。由于样品质量直接影响结果数据，目前的样品制备方法也在优化。现有的收集核磁共振数据的技术不足以实现该项目的目标，因此正在开发和改进新的核磁共振和样品制备技术，以收集结构确定所需的数据。目前正在作出相当大的努力，从样品中的所有类型的核中提取结构信息，尽管它们之间存在着强相互作用的固有问题。得到的短程和长程约束被输入到结构计算程序中。纤维形成的动力学和热力学也正在被深入研究。从两个方面处理这个问题，可以更好地理解有时收集到的含糊或复杂的数据。利用几种生化和生物物理技术的信息，不断地测试和改变纤维形成的工作模型。

0402114FlindersThe International Research Fellowship Program enables U.S. scientists and engineers to conduct three to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-two-month research fellowship by Dr. Jeremy C. Flinders to work with Dr. Hartmut Oschkinat at Institute for Molecular Pharmacology in Berlin, Germany.Amyloid fibrils are misfolded protein aggregates associated with a number of serious diseases, including prion and Alzheimer's disease, type II diabetes, and Huntington's disease. The exact mechanism of formation for these fibrils is currently not understood, primarily due to a lack of sufficient atomic-level structural information. The structures formed by such misfolding have traditionally been difficult to study, since they comprise long, thin filaments that are insoluble and do not crystallize. They are, however, suitable for study using recent solid-state nuclear magnetic resonance (NMR) techniques. The focus of this research project is determining the high-resolution structure of a model amyloid system and using this information to investigate fibril formation. Since sample quality directly affects the resulting data, current methods of sample preparation are also being optimized. Existing techniques for collecting NMR data are not sufficient for the goals of this project, therefore novel NMR and sample preparation techniques are being developed and refined to gather the needed data for structure determination. Considerable effort is being made to extract structural information from all types of nuclei in samples, despite inherent issues of strong interactions among them. Short and long-range distance constraints obtained are being inputted into structure calculation programs. Also being intensely studied is the kinetics and thermodynamics of fibril formation. Approaching this problem from two fronts allows for a better understanding of the sometimes ambiguous or complicated data collected. A working model of fibril formation is constantly being tested and altered using information from several biochemical and biophysical techniques.