Transcriptional Control of Alkaloid Biosynthesis in Catharanthus roseus Cultures

长春花培养物中生物碱生物合成的转录控制

• 批准号: 1033889
• 负责人: Carolyn Lee-Parsons
• 金额: $ 54.62万
• 依托单位: Northeastern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1033889&HistoricalAwards=false
• 关键词: Transcriptional; Control; Alkaloid; Biosynthesis; Catharanthus

This NSF award by the Biotechnology, Biochemical, and Biomass Engineering program supports research to 1) better understand how the cell regulates the production of medicinal alkaloids from cultures of the Madagascar periwinkle plant (Catharanthus roseus) and 2) use a new strategy based on gene silencing to enhance the production of these critical pharmaceutical compounds. Intellectual Merit: This project will improve the production of terpenoid indole alkaloids (TIAs) in cultures of Catharanthus roseus. C. roseus produces several highly-valued pharmaceuticals, including the anti-cancer drugs vincristine and vinblastine, but the slow growth rate of the plant and the low concentration of product are significant barriers to efficient drug production. The high cost and need for these pharmaceuticals motivate our research to better understand their biosynthesis and ultimately overproduce these compounds using C. roseus cultures. The goals of the proposed research are to describe the transcriptional regulation of enzymes required for TIA biosynthesis and to design an effective engineering strategy for overcoming innate blocks to TIA biosynthesis. The specific aims of this research are 1) to develop transgenic C. roseus hairy root cultures with altered expression of transcriptional regulators, 2) to characterize the alkaloid profiles and transcriptional profiles of genes relevant to TIA biosynthesis, and 3) to gain insight into the molecular mechanism of TIA production. Understanding the transcriptional regulation of TIA biosynthesis will provide the basis for new genetic engineering strategies for enhancing TIA production from C. roseus cultures. Broader Impact: The vision of this research is to address the need for an alternative supply of critical plant-derived pharmaceuticals using plant cell cultures. Increasing the volumetric productivity of these pharmaceuticals from plant cell cultures will reduce the cost of the drug to the patient and enable a dependable supply of the drug. In addition, the PI/Co-PI will 1) incorporate concepts and examples from their research into their courses and develop new lab modules, 2) co-advise graduate students and undergraduates in interdisciplinary research that applies biochemical engineering, genetic engineering, and molecular biology approaches to this research, and 3) support K-12 STEM education by hosting teachers and students through hands-on research experiences in their laboratory.

这项由生物技术、生化和生物质工程计划颁发的NSF奖支持以下研究：1)更好地了解细胞如何调节马达加斯加长春花(长春花)培养物中药用生物碱的生产；2)使用基于基因沉默的新策略来提高这些关键药物化合物的产量。智力价值：该项目将提高长春花培养物中萜类吲哚生物碱(TIA)的产量。玫瑰花生菌生产几种价值很高的药物，包括抗癌药物长春新碱和长春花碱，但植物生长速度慢，产物浓度低，是高效药物生产的重大障碍。这些药物的高成本和需求促使我们的研究更好地了解它们的生物合成，并最终利用玫瑰红曲霉培养大量生产这些化合物。这项研究的目的是描述TIA生物合成所需的酶的转录调控，并设计一种有效的工程策略来克服TIA生物合成的先天障碍。本研究的具体目的是：1)建立转录调控基因表达改变的转基因月季毛状根培养物；2)研究TIA生物合成相关基因的生物碱谱和转录谱；3)深入了解TIA产生的分子机制。了解TIA生物合成的转录调控将为新的基因工程策略提高玫瑰红曲霉TIA的产量提供基础。更广泛的影响：这项研究的愿景是解决使用植物细胞培养的关键植物衍生药物的替代供应的需求。提高这些来自植物细胞培养物的药物的体积生产率将降低患者的药物成本，并使药物能够可靠地供应。此外，PI/Co-PI将1)将他们研究中的概念和实例纳入他们的课程并开发新的实验单元，2)在将生化工程、基因工程和分子生物学方法应用于这项研究的跨学科研究中共同为研究生和本科生提供建议，以及3)通过在他们的实验室中接待教师和学生实践研究经验来支持K-12 STEM教育。