Research

中文說明請移至頁尾。

My research interests are the interplay of biomolecular interactions which are often crucial to cellular function and the malfunction of the interplays ultimately lead to human diseases.  The main focus of my research is post translational modifications (PTM) and epigenetics. PTMs are also the strength of my affiliated institute (IBC, Institute of Biological Chemistry, Acadmeia Sinica).  There are several outstanding groups in IBC working on glycosylation, (de)ubiquitination, (de)phosphorylation, autophagy and methylation. My group has close collaborations with PTM groups inside IBC and Academia Sinica as well.

The ubiquitin reaction cascade utilized E1, E2 and E3 enzymes. Ubiquitin like proteins, including ISG15, use similar cascade reactions.

My current research focuses on ubiquitination and its linked immune response. There are several ubiquitin-like (UBL) proteins in human genome. The particular one I am working on is call ISG15 (interferon-stimulated gene 15). ISG15 modifies viral or bacterial proteins (called ISGylation) followed by autoimmune response.  ISGylation one of the early defensive response to infectious pathogen.  My team utilizes biophysical and biochemical approaches to decode the mechanism of ISGylation. Our works will unveil new avenue, in addition to antibiotics, of drug development for infectious diseases.

ISGylation by ISG15 on viral NS1 protein is one of the early-step immune defense to stop virus replication.

The main biophysical tools used in my group can be accessed to several core facilities in Academia Sinica or national facilities supported by the MoST (Ministry of Science and Technology). In particular, biophysical core facility (BCF), nuclear magnetic resonance (NMR) and cryogenic electro-microscope (cryoEM) located on AS campus are convenient to us. We can also beam time at national synchrotron radiation research center (NSRRC) to access world top-ranked bright beam for X-ray diffraction.

NMR spectrometers in high field NMR center, IBMS, Academia Sinica
ASCEM’s Titan Krios cryogenic electron microscope (left), and it’s operation station (right top) and vitrobot for grid preparation (right bottom).

蛋白質泛素化、蛋白質類澱粉化與相關疾病藥物開發

我們的研究主題有二：
(1)蛋白質泛素化之機制探究，及相關連人類疾病之抗病藥物開發
後轉譯修飾在生物體內扮演了相當重要的功能調控角色。 舉凡磷酸修飾、甲基修飾、醣修飾等都是使用小分子直接在蛋白質的特定位置進行修飾。 然而泛素(ubiquitin)標記反應直接採用一個76顆氨基酸的小蛋白質(泛素)修飾在特定蛋白質上面。近半人體內的蛋白質都會被泛素修飾，絕大部分的泛素修飾產物會被帶往細胞內的蛋白酶體處理，如同細胞內的碎紙機把蛋白質絞碎後，回收氨基酸再利用。
我們近年專注於闡明泛素化跟病菌感染之免疫反應，新冠肺炎、登革熱、日本腦炎、感冒、肺結核等感染皆會改變細胞內的泛素化平衡，壓抑免疫力。藉由生物物理學、結構生物學、生物化學及合成生物學的技術，我們致力於闡明感染與泛素化機制，開發抗病菌藥物，提升本身的免疫反應。

(2)蛋白質類澱粉化與神經退化疾病的影響
諸多神經退化疾病都與蛋白質的類澱粉堆疊有關。其中帕金森氏症是僅次於阿茲海默症的神經退化疾病。導致神經退化而得到帕金森氏症的原因眾多，最常見的是腦細胞內的蛋白質 alpha-synuclein的長年性類澱粉化堆疊造成病變。導致alpha-synuclein類澱粉化堆疊的原因包含家族性遺傳、飲食來源、環境因子等，我們專注於探討此蛋白質從無序態逐步轉換成類澱粉化堆疊的過程，藉此找出關鍵的轉換機制，也致力於開發調控轉類澱粉化堆疊方法或藥物。