CAREER: Engineering Biomolecules and Cells for Oral Protein Delivery

职业：工程生物分子和细胞用于口服蛋白质递送

• 批准号: 1414483
• 负责人: Casim Sarkar
• 金额: $ 23.83万
• 依托单位: University of Minnesota-Twin Cities
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-30 至 2018-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1414483&HistoricalAwards=false
• 关键词: CAREER; Engineering; Biomolecules; Cells; Oral

Advances in biotechnology have made available recombinant forms of critically important therapeutic proteins. The idea of orally delivering such proteins is extremely attractive because this mode of administration is noninvasive, has higher patient compliance, and, in some cases, can more accurately mimic native physiology. However, due to major barriers encountered in the gastrointestinal tract - particularly harsh pH, rapid proteolytic degradation, and low intestinal permeability - proteins typically have very low bioavailability via oral delivery and are therefore routinely administered through an invasive method such as intravenous or subcutaneous injection. Here, a combined biomolecular and cellular engineering approach will be employed to overcome these bottlenecks and enhance oral protein delivery. This strategy will entail the development of general in vitro directed evolution approaches to enhance protein stability in the gastrointestinal tract as well as tunable synthetic biology approaches for engineering food-grade microorganisms to deliver these proteins orally. The specific application here is to create novel proteins and cells that can be used to orally regulate glucose levels in diabetic patients. These same protein engineering and synthetic biology approaches will also form the basis for a broadly reaching educational and training platform. Locally at the University of Pennsylvania, new educational modules will be incorporated into existing undergraduate and graduate courses, the first International Genetically Engineered Machine (iGEM) team will be created, and a new service learning course will be established to teach molecular biotechnology to inner-city high school students in Philadelphia. Nationally, high school teachers, undergraduates, and high school students will be recruited from underrepresented minority populations to carry out summer research projects. And internationally, impoverished street children in Mumbai, India will be introduced to principles of protein engineering and synthetic biology using examples that are of particular relevance to that population.

生物技术的进步使得重组形式的重要治疗蛋白成为可能。口服递送这种蛋白质的想法非常有吸引力，因为这种给药模式是非侵入性的，具有更高的患者依从性，并且在某些情况下，可以更准确地模拟自然生理。然而，由于胃肠道中遇到的主要障碍-特别是恶劣的pH值，快速的蛋白质水解降解和低肠通透性-蛋白质通过口服给药通常具有非常低的生物利用度，因此通常通过侵入性方法如静脉注射或皮下注射给药。在这里，将采用生物分子和细胞工程相结合的方法来克服这些瓶颈并增强口服蛋白质递送。这一策略将需要发展一般的体外定向进化方法，以提高胃肠道中蛋白质的稳定性，以及可调的合成生物学方法，用于工程食品级微生物口服传递这些蛋白质。这里的具体应用是创造新的蛋白质和细胞，可用于口服调节糖尿病患者的血糖水平。这些相同的蛋白质工程和合成生物学方法也将构成一个广泛影响的教育和培训平台的基础。在当地的宾夕法尼亚大学，新的教育模块将被纳入现有的本科和研究生课程，第一个国际基因工程机器（iGEM）团队将被创建，并将建立一个新的服务学习课程，向费城市中心的高中生教授分子生物技术。在全国范围内，高中教师、本科生和高中生将从代表性不足的少数民族中招募，开展暑期研究项目。在国际上，印度孟买的贫困街头儿童将被介绍蛋白质工程和合成生物学的原理，使用与该人群特别相关的例子。