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

本研究的完成将描述N-糖基化及其对肌肉细胞功能的调节的基本作用，使用重复的过程混合实验，统计和计算方法。糖基化--将糖残基共价添加到蛋白质上的过程--是对参与细胞通讯的蛋白质的常见修饰。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，从而表明糖基化在肌细胞生理学中的基本和动态作用。通过这项研究获得的新知识将被整合到实验和计算肌细胞生物学交叉点的跨学科教育计划中，该计划旨在吸引和留住学生科学家，重点关注代表性不足的群体的学生/学员。为此，将制定以下措施：1）关于实验和计算肌细胞生物学的大规模开放式在线课程，2）基于Web的用户友好的肌细胞模型和分析算法，3）肌细胞模型原型VR系统的初步工作，使研究人员和学生能够积极实践，感受，并与细胞机电功能进行真实的互动，以及4）为高中生提供心血管生理学的交互式实验室体验。最近的数据表明，调节糖基化，电信号和肌细胞收缩之间的联系。虽然由于缺乏适当的模型，这种假定联系的机制仍然难以捉摸，但在这里，将使用迭代过程来确定负责的细胞机制，该过程将已建立的生物物理和生物化学技术与新开发的糖组学方法、严格的计算机模拟建模、在新创建的更合适的动物模型上进行统计学实验设计，以描述糖组变化对心肌细胞生理学描述这样一种机制的影响和意义因物种间糖基化机制高度可变的事实而扩大。因此，存在于生物体中的差异糖基化可能导致蛋白质功能的调节，然后可预测地改变细胞活性。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

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.