Cells physiologic states are dictated by the collective behavior of thousands of molecular components and may vary dramatically depending on environmental factors, resulting in non-linear behaviors. Despite significant advances in systems and synthetic biology, protein function in cells remains hard to decipher due to the plasticity and adaptability of cellular regulatory and quality control mechanisms. The overarching goal of this project is to generate a platform technology to modulate the accumulation of target proteins in cells. This technology is expected to provide exquisite dynamic control over protein expression, thereby providing a tool to study protein function. A series of complementary strategies will be explored to achieve stimulus-dependent control over modulation of protein expression and to deploy this technology to study complex biological processes. As a result, this study is expected to promote progress of fundamental science , advance the bioeconomy, and enable advances in healthcare. By providing broad reaching educational and training opportunities to students belonging to underrepresented groups, this project is also expected to support education and diversity and to benefit society.
To overcome the limitations of existing methods for regulating protein steady state levels, the research team built a platform for modulating protein expression post-translationally using a bifunctional system consisting of a molecular recognition unit for target specificity and selectivity, and a degradation-signaling unit that specifies the rate and mechanism of degradation of the target protein. The goal of the proposed research is to engineer this technology to generate a universal platform for controlling protein levels through exogenous or endogenous stimuli. To achieve this goal, three research objectives will be pursued: 1) engineer stimulus-responsive degradation of protein depletion, 2) enhance the dynamic resolution of stimulus-dependent circuits through controlled reporter depletion, and 3) decipher and manipulate the hypoxia signaling network. This research program will be leveraged to provide training, research, and mentoring opportunities for high school teachers and students from the Greater Houston area, and to improve teaching and learning for college students.
