CAREER: Enabling nanodisc native mass spectrometry to study membrane active compounds

人体内的细胞不断受到入侵者的攻击，包括细菌，病毒和环境中的某些分子。虽然已知膜活性化合物（MAC）通过与入侵者的细胞膜相互作用来保护人类细胞，但它们究竟是如何做到这一点的仍然不清楚。亚利桑那大学的Michael Marty博士使用质谱法来了解膜活性化合物的行为，从而为人体免疫系统的功能提供了基本的见解。该项目使用新的质谱工具来确定MAC如何改变细胞膜模拟物的结构和稳定性。一系列综合教育活动提供质谱数据分析方面的专业培训，同时让退伍军人参与科学教育和研究活动。该计划简化了退伍军人从兵役到高等教育的过渡，促进了STEM教育（STEM）的持续性，并扩大了研究的参与。该奖项的设立也是为了加强教育基础设施，扩大数据分析技术的传播。有了这个奖项，生命过程化学项目，与化学测量和成像项目共同资助，正在资助亚利桑那大学的迈克尔·马蒂博士研究直接靶向脂质膜的膜活性化合物（MAC）。 在过去，这些作用机制没有得到很好的理解，因为它是难以量化的MAC膜内的相互作用。Marty博士正在通过开发基于天然质谱（MS）方法和脂蛋白纳米盘膜模拟物的新型化学测量技术来应对这一挑战。通过测量具有嵌入的MAC复合物的整个纳米盘组件的质量，可以表征MAC在不同脂质环境中的低聚状态。这个CAREER项目通过揭示在原生MS条件下纳米盘稳定性的机制，创建模拟天然膜的原生MS兼容纳米盘，以及开发用于分析复杂MS数据的算法，为这些实验提供了基础。研究目标与两个教育目标相结合，涉及本科退伍军人参与STEM研究和专业教育教程的开发。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

Cells within the human body are consistently under attack by invaders, which include bacteria, viruses, and certain molecules in the environment. While it is known that membrane-active compounds (MACs) defend human cells by interacting with the invader's cell membranes, exactly how they do this is still unclear. Dr. Michael Marty of the University of Arizona uses mass spectrometry to gain an understanding of membrane-active compound behavior and thus, provides fundamental insight into how the body's immune system functions. This project uses new mass spectrometry tools to determine how MACs change the structure and stability of cell membrane mimics. A set of integrated educational activities provide professional training in mass spectrometry data analysis while engaging military veterans in science education and research activities. The program eases the transition of veterans from military service to higher education, promotes persistence in STEM education (STEM), and broadens participation in research. Tutorials are also created to enhance the educational infrastructure and broaden the dissemination of data analysis technologies.With this award, the Chemistry of Life Processes Program, with co-funding from the Chemical Measurement and Imaging Program, is funding Dr. Michael Marty at the University of Arizona to study membrane-active compounds (MACs) that directly target lipid membranes. In the past, these mechanisms of action were not well understood because it is difficult to quantify MAC interactions within membranes. Dr. Marty is addressing this challenge through the development of novel chemical measurement techniques based on native mass spectrometry (MS) methods and lipoprotein nanodisc membrane mimetics. By measuring the mass of the entire nanodisc assembly with embedded MAC complexes, it is possible to characterize the oligomeric states of MACs in different lipid environments. This CAREER project provides the foundation for these experiments by uncovering the mechanisms of nanodisc stability under native MS conditions, creating native MS-compatible nanodiscs that model natural membranes, and developing algorithms for the analysis of complex MS data. The research objectives are integrated with two educational objectives that involve the engagement of undergraduate military veterans in STEM research and the development of professional education tutorials.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.