The general research interests of my laboratory are at the interface of organic chemistry, biochemistry and molecular biology. Nucleic Acids play the most important roles in living organisms, therefore, to understand how nucleic acids behave in vitro and in vivo is essential to understand their biochemical and biological functions. My research projects integrate synthetic skills, enzymatic methods and molecular and structural biology techniques to better understand structural properties and molecular mechanisms of nucleic acids. Current projects are related to synthesis of analogs of nucleosides and nucleotides, selenium-derivatized nucleic acids (SeNA), derivatization of DNA and RNA for nucleic acid X-ray crystallographic studies, in vitro and in vivo selection and evolution of ligand-binding and catalytic RNAs, ribozyme gene therapy, and MicroChip development for direct detection of human diseases and pathogens. Via our chemogenetic studies, SeNA research creates a novel paradigm of nucleic acids.

Project I: Selenium Derivatization of DNA & RNA and X-ray Crystallography

DNA & RNA Se-Derivatization and X-ray Crystallography: X-ray crystallography is a powerful tool for structure determination of RNA structure, RNA-protein and DNA-protein complexes with high resolution. Derivatization with heavy atoms for phase determination, a long-standing problem in X-ray crystallography, however, has largely slowed down structural determination of nucleic acids with novel folds. One approach to facilitate the structure determination is to label nucleic acids with covalently linked heavy atoms, which enable phase and structure determination. We have developed a novel strategy to derivatize RNA and DNA by replacing oxygen with selenium, and this principle has been demonstrated by X-ray crystallography using MAD phasing method. We are derivatizing DNA and catalytic and binding RNA sequences with novel folds, via chemical and enzymatic synthesis, for X-ray crystallographic studies of nucleic acids and their protein complexes. This novel strategy will revolutionize Nucleic Acid X-ray Crystallography.

Project II: RNA MicroArray and MicroChip Technologies for Functional Genomics

RNA MicroArray and MicroChip Technologies: Rapid research progress in genome sequence and function has facilitated drug discovery and revealed insights on infection, disease mechanism, and cancer subtype via gene expression profiling. My laboratory has recently developed a novel RNA detection and quantification method, which involves the RNA 3’-terminal labeling. This specific labeling and detection approach have lead to an RNA detection method on microplate via immobilization of the hybrid template. The microplate format dramatically simplifies the experimental procedure. On the basis of this successful novel strategy, we are in a process of developing RNA microchip technology. It is envisioned that this RNA MicroChip Technology will be simple, rapid, accurate, sensitive, high-throughput, and cost-effective and that it will be an ideal approach for pathogen detection in biodefense, cancer diagnosis and research, drug target validation and development, point-of-care disease diagnosis, SNP analysis, and detection of closely-related microorganisms and strains in air, soil, food, and water supply.