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/FERNANDEZINTELTECTUAL功能该项目旨在奠定基础，以填补对非本地微粒形成的机械理解与溶解聚集体的形成，凝聚相分离的热力学的形成，以及稳定聚集的聚集体和控制量和控制量和控制量和控制量和控制量和控制。模型蛋白质系统是α-偶联丙糖蛋白酶原A（ACGN）和人类免疫球蛋白γ-1（IgG1-FC）的FC区域。 ACGN是基于其可溶性骨料形成的确定机制及其形成聚集体和微粒的经验能力的良好的起点。 IgG1-FC是可在商业上可行的蛋白质的有用桥梁，因为它是基于单克隆抗体（MABS）或融合构建体的一系列生物制药蛋白质中的一个关键领域，并且初步数据还表明，它既易于构成可溶性的聚集物和颗粒的影响力又有很高的影响力，并且在较高的范围内构成了较高的影响力。拟议的研究将导致对聚集和颗粒形成的机理理解。从而为PI的实验室以及其他人的未来努力提供了基础，以合理设计和控制聚集抗性，以及控制主要类别的生物技术产品（例如mAbs和抗体 - 融合蛋白）的聚集和粒子结构 /形态。该协作研究计划涉及Amgen的Co-Pi的大量学生指导和科学贡献，包括扩展的学生实习和常规团队会议。通过这些合作，包括在学术机构中的工作，该项目将为PIS实验室的研究生和本科生的教育和培训提供一个框架，并特别关注尖端的实验和建模工具。与过去一样，UVA和UD的PI将涉及从代表性不足的科学和工程中吸引的学生。最后，将开发一组示例和问题，以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。这些模块将通过由圣何塞州立大学（San Jose State University）领导的基于网络的教育材料存储库传播到其他教师，该材料由弗吉尼亚州的一个PI共同开发。