RII Track-2 FEC: Advanced Biomanufacturing: Catalyzing Improved Host Development and High Quality Medicines through Genome to Phenome Predictions

RII Track-2 FEC：先进生物制造：通过基因组到表型组预测促进宿主发育和高质量药物的改进

• 批准号: 1736123
• 负责人: Sarah Harcum
• 金额: $ 600万
• 依托单位: Clemson University
• 依托单位国家: 美国
• 项目类别: Cooperative Agreement
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1736123&HistoricalAwards=false
• 关键词: RII; Track; FEC; Advanced; Biomanufacturing

Non-technical descriptionThis Research Infrastructure Improvement Track-2 Focused EPSCoR Collaborations (RII Track-2 FEC) award brings together Clemson University, University of Delaware, Tulane University, and Delaware State University to develop new biological approaches to better understand the Chinese hamster ovary (CHO) cell line, which is used to manufacture most biopharmaceuticals. For example, CHO cells are used to manufacture more than 50% of biopharmaceuticals, and products from CHO cells have global sales over $70 billion per year. A lack of understanding of the fundamental link between genome stability and the phenome significantly limits the ability to improve cell lines and ultimately increase product yields. This project will provide foundational knowledge linking the genome (what is in the chromosome or DNA) to what is observed (the phenome). This award provides the opportunity for investigators with complementary expertise to collaborate in advance of developing bio-manufacturing knowledge. Additionally, this project will mentor four early-career tenure-track underrepresented minority (URM) faculty and train postdoctoral scholars and graduate and undergraduate students. The project?s vision is to create a sustainable, high impact, collaborative research team from three EPSCoR jurisdictions that innovates fundamental genome-phenome knowledge and solves biopharmaceutical manufacturing challenges to: 1) improve patient access to medicines; 2) develop a highly skilled, diverse, and inclusive workforce; and 3) acquire fundamental genome to phenome knowledge applicable to any biological system.Technical descriptionChinese hamster ovary (CHO) cells are the most widely used mammalian host cell line to manufacture biopharmaceuticals, including infliximab to treat Crohn's disease and erythropoietin (EPO) to treat severe anemia. These cell lines provide a unique opportunity to quantitatively address the complex interactions between the genome and phenome because these cells can be cultured in very tightly controlled environments (bioreactors) to generate variable phenomes due to genome instability. This project focuses on studying the basis for genomic instability in CHO cells and aims to expand the quantitative understanding of the complex interactions between the genome and environment that generates the variable phenotypes. This project will strengthen existing collaborations among academics and provide mentoring for URM tenure-track faculty members at four institutions in South Carolina, Delaware, and Louisiana. Together, these researchers will develop systems biology approaches to understand and re-engineer the genome-phenome relationship and apply this knowledge to advance the ability to manufacture biopharmaceuticals. The project will: 1) expand the research infrastructure in participating institutions; 2) build individual and collective competence graduate students in genome-phenome knowledge and CHO cell cultivation and engineering; 3) share genome-phenome knowledge and tools that could be applicable to any other organism whether or not it has issues with genome stability; 4) broaden and foster the participation of tenure-track early-career underrepresented minority (URM) faculty members; and 5) provide research experiences for URM students and establish students exchanges among the participating EPSCoR jurisdictions.

非技术支持这一研究基础设施改进轨道-2重点EPSCoR合作（RII轨道-2 FEC）奖汇集了克莱姆森大学，特拉华州大学，杜兰大学和特拉华州州立大学，以开发新的生物学方法，以更好地了解中国仓鼠卵巢（CHO）细胞系，这是用来制造大多数生物药品。 例如，CHO细胞用于制造超过50%的生物制药，并且来自CHO细胞的产品每年的全球销售额超过700亿美元。 缺乏对基因组稳定性和表型组之间的基本联系的理解显著限制了改善细胞系和最终提高产物产量的能力。该项目将提供将基因组（染色体或DNA中的内容）与观察到的内容（表型组）联系起来的基础知识。 该奖项为具有互补专业知识的研究人员提供了在开发生物制造知识之前进行合作的机会。 此外，该项目将指导四个早期职业终身制轨道代表性不足的少数民族（URM）教师和培养博士后学者和研究生和本科生。 项目？我们的愿景是创建一个可持续的，高影响力的，来自三个EPSCoR司法管辖区的合作研究团队，创新基础基因组-表型组知识，解决生物制药制造挑战：1）改善患者获得药物; 2）发展高技能，多样化和包容性的劳动力;获得适用于任何生物系统的基本基因组至表型组知识。技术说明中国仓鼠卵巢（CHO）细胞是最广泛使用的哺乳动物宿主细胞系，用于生产生物药物，包括治疗克罗恩病的英夫利昔单抗和治疗严重贫血的促红细胞生成素（EPO）。这些细胞系提供了一个独特的机会来定量地解决基因组和表型之间的复杂相互作用，因为这些细胞可以在非常严格控制的环境（生物反应器）中培养，以产生由于基因组不稳定性而可变的表型。该项目的重点是研究CHO细胞中基因组不稳定性的基础，旨在扩大对基因组与产生可变表型的环境之间复杂相互作用的定量理解。该项目将加强学者之间的现有合作，并为南卡罗来纳州，特拉华州和路易斯安那州的四个机构的URM终身教职员工提供指导。 这些研究人员将共同开发系统生物学方法来理解和重新设计基因组-表型组关系，并应用这些知识来提高制造生物制药的能力。该项目将：1）扩大参与机构的研究基础设施; 2）培养基因组-表型组知识和CHO细胞培养和工程方面的个人和集体能力研究生; 3）分享基因组-表型组知识和工具，这些知识和工具可以适用于任何其他生物体，无论其是否存在基因组稳定性问题; 4）扩大和促进终身制早期职业代表性不足的少数民族（URM）教师的参与;和5）为URM学生提供研究经验，并在参与的EPSCoR司法管辖区之间建立学生交流。

项目成果

Controlling the Glycosylation Profile in mAbs Using Time-Dependent Media Supplementation

使用时间依赖性培养基补充来控制 mAb 中的糖基化特征

• DOI: 10.3390/antib7010001
• 发表时间: 2018
• 期刊: Antibodies
• 影响因子: 4.7
• 作者: Radhakrishnan, Devesh;Robinson, Anne;Ogunnaike, Babatunde
• 通讯作者: Ogunnaike, Babatunde

Text Mining of CHO Cell Bibliome: Topic Modeling and Document Classification

CHO Cell Bibliome 的文本挖掘：主题建模和文档分类

• 发表时间: 2022
• 期刊: bioRxiv
• 作者: Wang, Qinghua;Olshin, Jonathan;Vijay-Shanker, K.;Wu, Cathy
• 通讯作者: Wu, Cathy

Method for high-efficiency fed-batch cultures of recombinant Escherichia coli.

重组大肠杆菌的高效补料分批培养方法。

• DOI: 10.1016/bs.mie.2021.05.004
• 发表时间: 2021
• 期刊: Methods in enzymology
• 作者: T. Caldwell;Benjamin F Synoground;S. Harcum
• 通讯作者: S. Harcum

Comprehensive assessment of host cell protein expression after extended culture and bioreactor production of CHO cell lines

CHO细胞系扩展培养和生物反应器生产后宿主细胞蛋白表达的综合评估

• DOI: 10.1002/bit.28128
• 发表时间: 2022
• 期刊: Biotechnology and Bioengineering
• 影响因子: 3.8
• 作者: Hamaker, Nathaniel K.;Min, Lie;Lee, Kelvin H.
• 通讯作者: Lee, Kelvin H.

A reference genome of the Chinese hamster based on a hybrid assembly strategy.

• DOI: 10.1002/bit.26722
• 发表时间: 2018-08
• 期刊: Biotechnology and bioengineering
• 影响因子: 3.8
• 作者: Rupp O;MacDonald ML;Li S;Dhiman H;Polson S;Griep S;Heffner K;Hernandez I;Brinkrolf K;Jadhav V;Samoudi M;Hao H;Kingham B;Goesmann A;Betenbaugh MJ;Lewis NE;Borth N;Lee KH
• 通讯作者: Lee KH