EAPSI: Understanding Alzheimer's Disease through Modifying the Electrical Stability between Two Key Amino Acids of an Important Protein

EAPSI：通过改变重要蛋白质的两个关键氨基酸之间的电稳定性来了解阿尔茨海默病

• 批准号: 1515384
• 负责人: Kevin Chen
• 金额: $ 0.51万
• 依托单位: Chen Kevin H
• 依托单位国家: 美国
• 项目类别: Fellowship Award
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1515384&HistoricalAwards=false
• 关键词: EAPSI; Understanding; Alzheimer; Disease; through

Alzheimer's disease (AD) is a progressive, neurodegenerative disease that affects 5 million elderly Americans and this number is expected to triple by 2050. AD is currently the 6th leading cause of death in the United States. Despite decades of AD research, there is no cure for this deadly disease. A significant challenge in AD research is studying the mechanism that makes an ordinary protein transform from its natural, non-toxic state to an abnormal, toxic form. Often, differences in protein structure can lead to drastically altered biological activities. Unfortunately, this rapid transition between the two distinct structural identities is not well understood. Experimental evidence suggests that there are favorable molecular interactions that stabilize the abnormal form. This award supports research that aims to study the electrical interaction between two key amino acids of an important AD protein, amyloid-beta, in order to evaluate the protein's structural stability. The research will be conducted at National Taiwan University under the mentorship of Dr. Richard Cheng, whose expertise in one of the experimental techniques will be critical to the outcome of the project.The experimental design of this basic Alzheimer's disease research integrates the specialties from both the home and host laboratories. A series of peptide structural models of amyloid-beta will be synthesized using standard solid-phase peptide synthesis followed by product purification and characterization. These synthetic peptides will incorporate fragments of amyloid-beta that are known to initiate uncontrolled aggregation which can be subsequently suppressed by a well-placed hydrogen-bond blocker. To probe the electrostatic interaction between two key amino acids (lysine and glutamic acid) of amyloid-beta, they will be systematically replaced by amino acid derivatives. The modifications should either enhance or reduce the electrostatic interaction, which can lead to structural stabilization or destabilization of these peptides, respectively. Circular dichorism spectroscopy, a specialty of Dr. Cheng, will be used to quantify the stabilizing energies. The results of this project will afford deeper insights of a key molecular interaction that can stabilize the toxic form of amyloid-beta. This information may assist other AD researchers in their own endeavors and lead to future Alzheimer's disease discoveries that will benefits society. This NSF EAPSI award supports the research of a U.S. graduate student and is funded in collaboration with the Ministry of Science and Technology of Taiwan.

阿尔茨海默病（AD）是一种进行性神经退行性疾病，影响500万美国老年人，预计到2050年这一数字将增加两倍。AD目前是美国第六大死亡原因。尽管几十年的AD研究，没有治愈这种致命的疾病。AD研究中的一个重大挑战是研究使普通蛋白质从其天然无毒状态转变为异常有毒形式的机制。通常，蛋白质结构的差异会导致生物活性的急剧改变。不幸的是，这两个不同的结构身份之间的快速转变并没有得到很好的理解。实验证据表明，有有利的分子相互作用，稳定的异常形式。该奖项支持旨在研究一种重要的AD蛋白-淀粉样蛋白-β的两个关键氨基酸之间的电相互作用的研究，以评估蛋白质的结构稳定性。这项研究将在国立台湾大学进行，由Richard Cheng博士指导，他在一项实验技术方面的专业知识将对项目的结果至关重要。这项基础阿尔茨海默病研究的实验设计整合了家庭和主机实验室的专业知识。淀粉样蛋白β的一系列肽结构模型将使用标准固相肽合成法合成，然后进行产物纯化和表征。这些合成肽将掺入已知引发不受控制的聚集的淀粉样蛋白-β的片段，所述不受控制的聚集随后可被适当放置的氢键阻断剂抑制。为了探测淀粉样蛋白β的两个关键氨基酸（赖氨酸和谷氨酸）之间的静电相互作用，它们将被氨基酸衍生物系统地取代。所述修饰应增强或减少静电相互作用，这可分别导致这些肽的结构稳定化或不稳定化。圆二色光谱学是郑博士的专长，将用于量化稳定能量。该项目的结果将提供更深入的了解一个关键的分子相互作用，可以稳定淀粉样蛋白β的毒性形式。这些信息可能有助于其他AD研究人员自己的努力，并导致未来阿尔茨海默病的发现，这将有利于社会。这个NSF EAPSI奖支持美国研究生的研究，并与台湾科技部合作资助。