Proteins are used to treat a wide variety of diseases. These include several cancers, kidney failure and rheumatoid arthritis, to name a few. Production of therapeutic proteins has increased dramatically over the last decade and is expected to continue to rise for the next decade as treatments are developed for a larger number of diseases. Most of these proteins are produced from mammalian cells, which are the most capable of producing proteins with activity in humans. However, they are also limited in their ability to manufacture protein at large scale. This project will evaluate a number of strategies designed to increase protein production in mammalian cells. Education and training opportunities will target high school teachers and students from the Greater Houston area. This will enhance and diversify the pipeline of a STEM-ready workforce.
Many complex recombinant proteins are manufactured in mammalian cells. The yield depends both on cell productivity and cell growth. Overexpression of recombinant proteins causes the accumulation of misfolded proteins and proteotoxic stress. These, in turn, lead to activation of a global response that may ultimately inhibit protein synthesis and reduce cell viability. This response culminates in the stimulation of protein degradation. The fate of the cell depends on the relative rates of activation of the signaling pathways involved in the response. The project team will use a recently-developed in-house technology to monitor gene expression with high sensitivity and dynamic resolution. Expression of markers of the protein quality control system upon overexpression of representative recombinant proteins will be profiled. Results will be used to generate strategies to remodel the stress response pathway, enhance quality control, and delay cell death in cells expressing high levels of recombinant proteins. Because of the fundamental role of the stress response in maintaining cellular homeostasis, results from this study will impact the design of a variety of cell engineering applications.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
