The long-term objective of our research program is to develop and apply a new molecular approach to disease treatment. Therefore, activities and projects in the laboratory are organized along two intersecting dimensions: biotechnological development and biomedical application. We have been creating and using RNA aptamers that bind tightly to specific protein targets to control biological processes in living cells and organisms. The immediate application of this strategy is to evaluate particular proteins as potential drug targets. The specific problems we work on are related to potential treatment of malignant human tumors. Experiments in the lab utilize multiple cell lines and organisms as model systems.
Our understanding of sophisticated biological processes relies on the elucidation of the molecular mechanisms involved. One effective strategy to study these mechanisms in vitro and in vivo is to examine the consequences of altering specific genes or gene products, which are components of multi-protein assemblies or pathways. This approach in some cases may provide a simulation of certain diseased states; in other cases, it may suggest effective means of intervention to correct the malfunction—both scenarios may be used to validate drug targets. However, the existing tools that allow us to probe and perturb biological function have severe limitations. We seek to identify and to validate drug targets by modulating the function of many gene products in different pathways with temporal and spatial control in tissue culture cells or animals. Currently, we are studying two major types of breast cancer and a general cancer-enabling network.
On the systems level, the architecture of cellular regulatory networks is characterized by a "scale-free" topology, that is, most proteins interact with only one or a few other proteins, while a few proteins interact with many and serve as densely connected “hubs." This feature carries important implications concerning experimental and therapeutic control of cellular phenotypes, especially in the study and treatment of cancer and other severe diseases caused by somatic mutations. We have been developing new technologies that would enable us to “re-wire” these hubs. Specifically, we use aptamer-derived constructs to implement selective blockage of molecular interactions or selective creation of novel connections. These methods would spur therapeutic approaches difficult to implement by small molecules or polypeptides, and empower design-based predictive modification of cells and organisms.
Research in the Shi Lab has been supported by the American Cancer Society, the National Institutes of Health, and the US Department of Defense. Dr. Shi’s educational activities have been supported by the National Science Foundation and the National Center for Science and Civic Engagement.