GOALI: Collaborative Research: Structure, Stability, and Mechanisms of Nonnative Protein Aggregate & Microparticle Formation

目标：合作研究：非天然蛋白质聚集体的结构、稳定性和机制

• 批准号: 0932155
• 负责人: Erik Fernandez
• 金额: $ 33.28万
• 依托单位: University of Virginia Main Campus
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0932155&HistoricalAwards=false
• 关键词: GOALI; Collaborative; Research; Structure; Stability

0931173/0932155Roberts/FernandezIntellectual merit This project seeks to lay a foundation to fill key gaps in mechanistic understanding of the formation of nonnative microparticles vs. soluble aggregates, the thermodynamics of aggregate-particle phase separation, and key interactions that stabilize aggregates / particles and control their morphology. The model protein systems are alpha-chymotrypsinogen A (aCgn) and the Fc region of human immunoglobulin gamma-1 (IgG1-Fc). aCgn is a well-studied starting point, based on its established mechanisms of soluble aggregate formation, and its empirical ability to form both aggregates and microparticles. IgG1-Fc is a useful bridge to commercially viable proteins, as it is a key domain in a range of biopharmaceutical proteins that are based on either monoclonal antibodies (MAbs) or fusion constructs, and preliminary data also indicates it readily forms both soluble aggregates and particles.Broader impactsThe project addresses a long-standing and potentially very high impact problem in the biopharmaceutical industry. The proposed research will result in an improved mechanistic understanding of aggregation and particle formation; thereby providing a basis for future efforts in the PI's laboratories and those of others to rationally design and control aggregation resistance, as well as for control of aggregate and particle structure / morphology across major classes of biotechnology products such as MAbs and antibody-fusion proteins. The collaborative research plan involves significant student mentoring and scientific contributions from the co-PI from Amgen, including extended student internships and regular team meetings. Through these collaborations, including work in the academic institutions, this project will provide a framework for the education and training of graduate and undergraduate students in the PIs' laboratories, with a specific focus on cutting-edge experimental and modeling tools. As in the past, the PIs at UVA and UD will involve students drawn from underrepresented groups in science and engineering. Finally, a set of examples and problems will be developed to incorporate aspects of this research into the undergraduate curricula, including computational and modeling activities. These modules will be disseminated to other faculty via a web-based repository of educational materials led by San Jose State University that was co-developed by one PI at Virginia.

0931173/0932155Roberts/Fernandez智力价值该项目旨在奠定基础，以填补非天然微粒与可溶性聚集体形成的机械理解、聚集体-颗粒相分离的热力学以及稳定聚集体/颗粒和控制的关键相互作用的关键空白。他们的形态。模型蛋白质系统是 α-胰凝乳蛋白酶原 A (aCgn) 和人免疫球蛋白 gamma-1 (IgG1-Fc) 的 Fc 区。 aCgn 是一个经过充分研究的起点，基于其已建立的可溶性聚集体形成机制及其形成聚集体和微粒的经验能力。 IgG1-Fc 是商业上可行的蛋白质的有用桥梁，因为它是一系列基于单克隆抗体 (MAb) 或融合构建体的生物制药蛋白质的关键结构域，初步数据还表明它很容易形成可溶性聚集体和更广泛的影响该项目解决了生物制药行业长期存在且可能影响非常大的问题。拟议的研究将提高对聚集和颗粒形成机制的理解；从而为 PI 实验室和其他实验室未来合理设计和控制聚集抗性以及控制主要类别生物技术产品（如单克隆抗体和抗体融合蛋白）的聚集体和颗粒结构/形态奠定基础。该合作研究计划涉及安进联合首席研究员的重要学生指导和科学贡献，包括延长学生实习和定期团队会议。通过这些合作，包括在学术机构的工作，该项目将为 PI 实验室的研究生和本科生的教育和培训提供一个框架，特别关注尖端的实验和建模工具。与过去一样，UVA 和 UD 的 PI 将由来自科学和工程领域代表性不足群体的学生组成。最后，将开发一组示例和问题，将这项研究的各个方面纳入本科课程，包括计算和建模活动。这些模块将通过圣何塞州立大学领导的基于网络的教育材料存储库传播给其他教师，该存储库由弗吉尼亚州的一位 PI 共同开发。