BRIGE: Modeling metabolism in embryonic stem cell growth and differentiation

BRIGE：模拟胚胎干细胞生长和分化的代谢

• 批准号: 1125684
• 负责人: Mark Styczynski
• 金额: $ 17.5万
• 依托单位: Georgia Tech Research Corporation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1125684&HistoricalAwards=false
• 关键词: BRIGE; Modeling; metabolism; embryonic; stem

PI: Styczynski, MarkProposal Number: 1125684The research objective of this proposal is to measure and model the metabolism of embryonic stem cells during proliferation and differentiation. The PI's group is dedicated to understanding and controlling metabolism by studying and modeling metabolite concentrations. Here, we apply metabolite profiling and machine-learning techniques to create the first-ever descriptive models of metabolism in embryonic stem cell differentiation. We will also study the regulatory potential of metabolites we identify as significantly correlated with cellular differentiation.Intellectual MeritStem cells are poised to make a revolutionary impact on modern medicine. Given recent successes, attention has begun to turn to the looming biomanufacturing problem inherent in developing stem cell treatments. Difficulties expanding stem cell populations from small numbers and controlling their differentiation are such significant roadblocks to scale-up that stem cell therapies may be technically or economically infeasible on a large scale. One promising route for controlling stem cell behavior during scale-up is monitoring and manipulating metabolism and metabolic signals in these cells -yet there has been little research in this area. This transformative research plan will help fill this knowledge gap, specifically addressing three key issues in the field of stem cell culture and engineering. By performing a pioneering longitudinal metabolomics study, we will (1) establish an initial dataset and models demonstrating the importance of metabolism in stem cell expansion and differentiation, and that can be used in guiding culture scale-up. By identifying metabolites capable of promoting specific differentiation lineages, we will (2) enable more precise control of ES cells during expansion and differentiation, also facilitating scale-up. Finally, our extracellular metabolite profiling techniques and models will (3) provide non-invasive, non-destructive methods for stem cell culture monitoring and quality control that are capable of detecting changes in cell state long before morphological changes are evident.Broader ImpactsBy expanding capabilities in controlling stem cell fate using our systems-level analysis of metabolism, we will enable development of novel and more complex stem cell engineering therapeutics that can save or greatly improve the lives of people facing debilitating diseases. The direct application of our research results to the scale-up of stem cell culture technologies to industrial production levels will circumvent a critical economic roadblock in the field, enabling the development of therapeutic candidates into products that can heal not just those who are rich or fortunate, but anyone facing such a disease regardless of socioeconomic status. Such systems level analysis also has the potential to make a significant impact on future engineers; in this vein, the PI proposes a broadening participation program with a primary focus of encouraging female participation in engineering. The centerpiece of this effort is the development of an activity and event for Girl Scout troops that stokes interest in engineering and introduces them to the systems-level mindset that defines engineering. The PI will collaborate with a local teacher to develop this activity and align it with Georgia state educational standards. Female undergraduates and graduate students will help develop and implement this activity. Other key activities planned by the PI include continuing work with an all-female dormitory, collaboration with the campus Society of Women Engineers chapter in developing outreach activities, and recruiting and mentoring female students. Additionally, the PI's group will host underrepresented minority undergraduate students through an REU program; the first and third aims have been formulated to easily integrate undergraduate researchers in a rewarding project.

PI：Styczynski，商标编号：1125684该提案的研究目标是在增殖和分化过程中测量和建模胚胎干细胞的代谢。 PI的组致力于通过研究和建模代谢产物浓度来理解和控制代谢。在这里，我们应用代谢物分析和机器学习技术来创建胚胎干细胞分化中的新陈代谢的第一个描述性模型。我们还将研究代谢产物的调节潜力，我们确定为与细胞分化显着相关。智能优先系统细胞有望对现代医学产生革命性的影响。鉴于最近的成功，注意力已经开始转向开发干细胞处理固有的迫在眉睫的生物制造问题。从少数数量中扩大干细胞群体并控制其分化的困难是扩大规模的巨大障碍，以至于干细胞疗法在技术上或经济上可能在很大程度上是不可行的。在扩大规模期间控制干细胞行为的一种有希望的途径是监测和操纵这些细胞中的代谢和代谢信号 - 在该区域几乎没有研究。该变革性研究计划将有助于填补这一知识差距，特别解决干细胞培养和工程领域的三个关键问题。通过进行开创性的纵向代谢组学研究，我们将（1）建立一个初始数据集和模型，该数据集证明了代谢在干细胞扩张和分化中的重要性，并且可以用于指导培养文化规模。通过鉴定能够促进特定分化谱系的代谢产物，我们将（2）在扩展和分化过程中对ES细胞进行更精确的控制，还可以促进扩大规模。 Finally, our extracellular metabolite profiling techniques and models will (3) provide non-invasive, non-destructive methods for stem cell culture monitoring and quality control that are capable of detecting changes in cell state long before morphological changes are evident.Broader ImpactsBy expanding capabilities in controlling stem cell fate using our systems-level analysis of metabolism, we will enable development of novel and more complex stem cell engineering therapeutics that can save或大大改善面临衰弱疾病的人们的生活。我们的研究结果直接应用于干细胞培养技术在工业生产水平上的扩大规模，这将避免该领域的关键经济障碍，从而使治疗候选者能够发展为产品，不仅可以治愈那些富裕或幸运的人，而且无论如何都面临这种疾病，无论社会经济状况如何。 这种系统级分析还有可能对未来的工程师产生重大影响。在这种情况下，PI提出了一个扩大参与计划，主要是鼓励女性参与工程学。这项工作的核心是为女童子军部队开发一项活动和活动，该部队对工程学的兴趣兴趣，并将其介绍给定义工程学的系统级别的心态。 PI将与当地老师合作开发这项活动，并将其与佐治亚州的教育标准保持一致。 女性本科生和研究生将有助于开发和实施这项活动。 PI计划的其他关键活动包括继续与全女性宿舍一起工作，与校园女工程师协会合作开发外展活动，并招募和指导女学生。此外，PI的小组将通过REU计划主持代表性不足的少数族裔本科生；已经制定了第一个和第三个目标，可以轻松地将本科研究人员整合到一个有益的项目中。