Collaborative Research: Data-driven integration of biological with in-silico experiments to determine mechanistic effects of N-glycosylation on cellular electromechanical functions

这项研究的完成将描述N-糖基化的基本作用及其对肌肉细胞功能的调节，使用结合实验、统计和计算方法的重复过程。糖基化--将糖残基共价加到蛋白质上的过程--是对参与细胞通讯的蛋白质的一种常见修饰。生理信号调节糖基化过程，蛋白质糖基化影响心肌细胞的电和收缩功能，从而提示糖基化在肌肉细胞生理学中具有基础和动态的作用。通过这项研究获得的新知识将被整合到实验肌肉细胞生物学和计算肌肉细胞生物学交叉学科的教育计划中，该计划旨在吸引和留住学生科学家，重点是来自代表性不足群体的学生/受训人员。为此，将开发以下内容：1)关于实验和计算肌肉细胞生物学的大规模开放在线课程；2)基于Web的用户友好型心肌细胞模型和分析算法；3)使研究人员和学生能够主动练习、感受细胞机电功能并与其实时交互的肌细胞模型原型VR系统的初步工作；以及4)为高中生提供的心血管生理学互动实验室体验。最近的数据表明，调控的糖基化、电信号和心肌细胞收缩之间存在联系。虽然由于缺乏合适的模型，这种假定的联系的机制仍然难以捉摸，但在这里，负责的细胞机制将使用迭代过程来确定，该过程将现有的生物物理和生化技术与新开发的血糖学方法相结合，在新创建的更合适的动物模型上进行严格的计算机模拟和统计实验设计，以描述血糖变化对心肌细胞生理的功能影响。描述这种机制的影响和意义被物种间的糖基化机制高度可变的事实所扩大。因此，生物体之间存在的差异糖基化可能导致调节蛋白质功能，然后可预见地改变细胞活动。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Completion of this research will describe the fundamental roles for N-glycosylation and its regulation on muscle cell function using a repetitive process blending experimental, statistical, and computational methods. Glycosylation - the process of covalent addition of sugar residues to proteins - is a common modification to proteins involved in cellular communication. Physiological cues regulate the glycosylation process and protein glycosylation impacts electrical and contractile functions of cardiac muscle cells, thereby suggesting a fundamental and dynamic role for glycosylation in muscle cell physiology. The new knowledge gained through this research will be integrated into an interdisciplinary education program at the intersection of experimental and computational muscle cell biology that is aimed at engaging and retaining student scientists, focusing on students/trainees from underrepresented groups. To do so, the following will be developed: 1) A massive open online course on experimental and computational muscle cell biology, 2) Web-based user-friendly myocyte models and analytical algorithms, 3) Initial work on a prototype VR system of myocyte models that enable researchers and students to actively practice, feel, and interact with cellular electromechanical function in real time, and 4) An interactive laboratory experience in cardiovascular physiology for high school students. Recent data suggest a link among regulated glycosylation, electrical signaling, and myocyte contraction. While mechanisms for this putative link remain elusive due to a lack of appropriate models, here, the responsible cellular mechanisms will be determined using an iterative process that combines established biophysical and biochemical techniques with newly developed glycomic methods, rigorous in-silico modeling, and statistical experimental design on a newly created and more appropriate animal model to describe the functional impact of a changing glycome on cardiomyocyte physiology. The impact and significance of describing such a mechanism are broadened by the fact that the glycosylation machinery among species is highly variable. Thus, the differential glycosylation that exists among organisms likely results in modulated protein function that then predictably alters cellular activities.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.