CAREER: Understanding the Structure-Interaction-Reactivity Relationship between Small Molecules and Metal-Amyloid Species

通过这一职业奖，生命过程化学项目支持密歇根大学的Mi Hee Lim教授设计和合成化学库，以建立与金属相关的淀粉样β蛋白物种的结构和相互作用之间的关系。在这项研究计划中，林教授和她的学生将确定与金属离子、淀粉样β蛋白和金属淀粉样β蛋白相互作用所需的结构部分和支架。该研究小组将通过系统地修改小分子的结构来合成多种化学系列，这些小分子以前被证明与淀粉样β蛋白或金属淀粉样β蛋白相互作用和反应。新制备的分子与金属离子、淀粉样β蛋白和金属淀粉样β蛋白之间的相互作用将利用适当的分析方法，如紫外可见光谱、核磁共振光谱、质谱学和X射线结晶学，在全化学分辨率下进行表征。这项研究的结果将为开发适合于研究金属淀粉样β蛋白参与神经毒性导致的神经变性的化学工具的发展提供洞察力。由于目前尚不清楚金属离子与β-淀粉样蛋白之间的相互作用如何与神经毒性有关，因此有必要研制合适的化学工具来同时靶向金属-β-淀粉样蛋白并调节它们之间的相互作用。在进行这一研究计划时，LIM小组将为从高中到研究生水平的学生提供在生物无机化学领域进行跨学科研究的机会。传统上没有学习过这一领域的不同背景的学生不仅将被教授生物无机化学的概念，还将被介绍到实验室中令人兴奋的化学研究。林教授还将为女科学家(本科生到博士后)创造职业发展机会，特别关注与当地公司的接触，不同级别女化学家之间的对话，以及持续的沟通。通过这些努力，将鼓励未来的女科学家更多地参与科学工作，追求自己的职业目标。

With this CAREER Award the Chemistry of Life Processes program is supporting Professor Mi Hee Lim at the University of Michigan to design and synthesize chemical libraries to establish a relationship between structures and interactions with metal-associated amyloid-beta species. In this research program Professor Lim and her students will determine the structural moieties and scaffolds required for interactions with metal ions, amyloid-beta, and metal-amyloid-beta species. The research group will synthesize multiple chemical series via systematic structural modifications of small molecules previously demonstrated to interact and react with amyloid-beta or metal-amyloid-beta species. The interactions of newly prepared molecules with metal ions, amyloid-beta, and metal-amyloid-beta species will be characterized to full chemical resolution using appropriate analytic methods, such as UV-Visible and NMR spectroscopy, mass spectrometry (MS), and X-ray crystallography.The results of this research effort will provide insight into the development of chemical tools suitable for investigating the involvement of metal-amyloid-beta species in neurotoxicity leading to neurodegeneration. Since it is not well understood how the interactions of metal ions with amyloid-beta species could be associated with neurotoxicity, it is necessary to have appropriate chemical tools that can simultaneously target metal-amyloid-beta species and modulate their interactions. In pursuing this research program, the Lim group will provide opportunities for students from high school through graduate student level to conduct interdisciplinary research in bioinorganic chemistry. Students with diverse backgrounds who traditionally have not studied this field will not only be taught the concepts of bioinorganic chemistry, but also will be introduced to exciting chemistry research in the laboratory. Professor Lim will also create professional development opportunities for female scientists (undergraduate to postdoctoral), with special attention to outreach to local companies, dialogue among different levels of female chemists, and continuous communication. Through these efforts, future female scientists will be encouraged to enhance their involvement in the sciences and pursue their career goals.