助研究員 / 本院化學所

EDUCATION AND POSITIONS HELD:

• B.S. Physics, National Taiwan University (1989)
• M.A. Biophysics, University of California, Berkeley (1993)
• Ph.D. Biophysics, Stanford University (2001)
• Assistant Fellow, Chemistry, Academia Sinica (2003-present)
• Postdoctoral Fellow, Stanford University (2001-2003)
• Research Assistant, Stanford University (1993-2000)
• Research Assistant, IAMS, Academia Sinica (1991-1992)

RESEARCH INTERESTS:

Chemical basis of eukaryotic gene expression

Mechanistic understanding of gene expression at the level of RNA metabolism will lead to new strategies that help cure diseases caused by its aberration, for example, cancers. Two chemical approaches are taken in developing therapeutic strategies, namely, structure-based drug design and assay-based high-throughput drug screening. Recently, great advance has been made in elucidating atomic structure of a multiple protein complex that serves as the core machinery of RNA synthesis initiation. An atomic map of the protein complex opens inroads for designing small molecules to up- or down-regulate RNA synthesis by modulating communication between the core machinery and transcription factors that specifically respond to different stimuli. Currently, we are focusing on structure and function analysis of a transcription initiation and DNA repair TFIIH helicase complex. We have formed 2-dimensional crystal of core TFIIH for crystallographic analysis by cryo electron microscopy (cryo-EM), a proven method to achieve structures of near atomic resolution. Alternatively, we are over-expressing TFIIH sub-complexes for X-ray crystallographic analysis.

High-throughput macromolecular structural genomics

In eukaryotic cells, proteins as products of 30,000 genes often organize into large complexes, called “somes”. At least hundreds of protein complexes are governed by stable subunit-subunit interactions of which functional interactions were detected by “yeast two-hybrid”, and physical interactions by “mass spectroscopy”. These complexes represent molecular basis of crossroads among diverse cellular networks and account for diseases of complex traits. 3-dimensional molecular envelopes of these complexes are required for integration of the rapid growing two-hybrid and spectroscopy data. The giant size and scarcity of these complexes determine cryo-EM of single molecules in native state, the structural method of choice. To this end, we are seeking to install an automated electron microscope with large area CCD to streamline digital data collection in the near future.

Development of nano-technology based biosensor

With the capability of detecting and manipulating virtually single molecules, nano technology is bringing revolutionary impact on genomic and proteomic research. It is mainly because nano-technology can cut down intensive labors, material demands and propagated errors inherent with traditional biological sample preparation and analyses. We are currently fabricating a new generation of nano-gold based molecular beacons for detecting RNA expression in vivo.

Development of novel imaging based functional assays

Single molecule fluorescence microscopy has emerged as a powerful method to reveal heterogeneous molecular dynamics and kinetics that are hidden in bulk measurement. We are aimed at using fluorescence microscopy based single molecule assay to address the interactions between nucleic acid processing enzymes and their inhibitors. For example, helicase and telomerase, are drug targets for controlling virus replication and cancer cell survival.

我們的研究著重於使用穿透式低溫電子顯微鏡解決蛋白質巨分子複合物的原子結構, 特別有興趣於基因轉錄因子; 此外我們也正在建構螢光顯微鏡以觀察單一酵素分子的構形變化;我們期待綜合蛋白質結構與動態的資訊將有助了解基本生化過程的機制及設計酵素抑制劑.