Hua Shi

Areas of Interest

• Molecular and cellular biology of transcription and signal transduction
• Aptamer-mediated multi-pathway control in living cells and organisms
• Drug discovery and development for cancer

Research

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.  

Publications

• Wang, S., Shepard, J., and Shi, H. (2010) An RNA-based transcription activator derived from an inhibitory aptamer. Nucleic Acids Research, doi: 10.1093/nar/gkp1227. 
• Mallik, P., Nishikawa, K., Millis, A., and Shi, H. (2010) Commandeering a biological pathway using aptamer­derived molecular adaptors. Nucleic Acids Research, doi: 10.1093/nar/gkp1207. 
• Huang, Z., Pei, W., Han, Y., Jayaseelan, S., Shekhtman, A, Shi, H., and Niu, L. (2009) One RNA aptamer sequence, two structures: a collaborating pair that inhibits AMPA receptors. Nucleic Acids Research, 37, 4022-4032. 
• Xu, D. and Shi, H. (2009) Composite RNA aptamers as functional mimics of protein. Nucleic Acids Research, 37, e71. 
• Sevilimedu, A., Shi, H., and Lis, J.T. (2008) TFIIB aptamers inhibit transcription by perturbing PIC formation at distinct stages. Nucleic Acids Research, 36, 3118-3127.
• Huang, Z., Pei, W.M., Jayaseelan, Shi, H., and Niu, L. (2007) RNA aptamers selected against the GluR2 AMPA receptor channels expressed in HEK-293 cells. Biochemistry, 46, 12648-12655.
• Shi, H. [co-corresponding author], Fan, X., Sevilimedu, A., and Lis, J.T. (2007) RNA aptamers directed to discrete functional sites on a single protein structural domain. Proc. Natl. Acad. Sci. USA, 104, 3742-3746. 
• Zhao, X., Shi, H., Sevilimedu,A., Liachko, N., Nelson, H., and Lis, J.T. (2006) An RNA aptamer that interferes with the DNA binding of the HSF transcription activator. Nucleic Acids Research, 34, 3763-3769.
• Fan, X., Shi, H., and Lis, J. T. (2005) Distinct transcriptional responses of RNA polymerases I, II, and III to aptamers that bind TBP. Nucleic Acids Research, 33, 838-845. 
• Fan, X., Shi, H. [co-first author], Adelman, K., and Lis, J. T. (2004) Probing TBP interactions in transcription initiation and reinitiation with RNA aptamers that act in distinct modes. Proc. Natl. Acad. Sci. USA, 101, 6934-6939. 
• Kim, S., Shi, H., Lee, D-k., and Lis, J. T. (2003) Specific SR protein-dependent splicing substrates identified through genomic SELEX. Nucleic Acids Research, 31, 1955-1961. 
• Shi, H. [co-corresponding author], Fan, X., Ni, Z., and Lis, J. T. (2002) Evolutionary dynamics and population control during in vitro selection and amplification with multiple targets. RNA, 8, 1461-1470.
• Shi, H., Hoffman, B. E., and Lis, J. T. (1999) RNA aptamers as effective protein antagonists in a multicellular organism. Proc. Natl. Acad. Sci. USA, 96, 10033-10038. 
• Ulrich, H., et al (1998) In vitro selection of RNA molecules that displace cocaine from the membrane-bound nicotinic acetylcholine receptor. Proc. Natl. Acad. Sci. USA, 95, 14051-14056. 
• Shi, H., Ziegelbauer, J. M., Hoffman, B. E., and Lis, J. T. (1997) Artificial genes expressing RNA aptamers as specific protein inhibitors in vivo. Nucleic Acids Symposium Series, No. 36, 194-196. 
• Shi, H., Hoffman, B. E., and Lis, J. T. (1997) A specific RNA hairpin loop structure binds the RNA recognition motifs of the Drosophila SR protein B52. Molecular and Cellular Biology, 17(5), 2649-2657.

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.