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

合作研究：数据驱动的生物与计算机实验相结合，以确定 N-糖基化对细胞机电功能的机械效应

基本信息

批准号：
1856199
负责人：
Eric Bennett
金额：
$ 77.4万
依托单位：
Wright State University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1856199&HistoricalAwards=false
关键词：
Collaborative Research Data driven integration

项目摘要

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.

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，使用重复的过程融合实验，统计和计算方法。糖基化 - 将糖残基与蛋白质共价添加过程 - 是对参与细胞通信的蛋白质的常见修饰。生理提示调节糖基化过程和蛋白质糖基化会影响心肌细胞的电和收缩功能，从而提出糖基化在肌肉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在实验和计算肌肉细胞生物学的交集中纳入跨学科教育计划，该计划旨在参与和留住学生科学家，重点是来自代表性不足的群体的学生/学员。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的用户友好型肌细胞模型和分析算法，3）3）在心肌细胞原型VR系统上的初步工作使研究人员和学生能够实时实践，感觉和与细胞机电功能进行积极练习，感觉和互动的模型，以及4）高中生心血管生理学的互动实验室经验。最近的数据表明，调节的糖基化，电信号传导和心肌收缩之间存在联系。尽管由于缺乏适当的模型，因此该推定链接的机制仍然难以捉摸，但在这里，将使用迭代过程确定负责任的细胞机制，该过程将已建立的生物物理和生化技术与新开发的糖化方法，严格的内部模型以及统计学建模以及统计学上的统计学结合，以及在新创建和更合适的动物模型上进行实验设计，以描述糖果不断变化的心肌细胞生理学的功能影响。描述这种机制的影响和意义是通过物种之间的糖基化机制高度可变的事实来扩展的。因此，存在于生物体之间存在的差异糖基化可能导致调制蛋白质功能，从而可以预测地改变了细胞活性。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的智力优点和更广泛影响的评估来审查标准的。