Transcriptional Control of Alkaloid Biosynthesis in Catharanthus roseus Cultures

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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.