Research
研究方向
research direction
研究室特色與研究方向:
(1)以整合性體學研究模式研發口腔癌早期診斷生物標記及精準治療標靶
口腔癌為國人好發癌症之一，男性發生率世界第一，已成為國人重大健康議題與醫療負擔。然而在過去二十年間，口腔癌的早期偵測與精準標靶治療進展非常有限，目前仍無有效的生物標記(biomarker)可應用於提高早期口腔癌檢出率及輔助術後追蹤，也缺乏針對口腔癌研發的標靶治療(target therapy)策略以提升個人化的治療效果。
本實驗室帶領分子醫學研究中心研究團隊，參與美國領導的國際癌症蛋白基因體聯盟(國際癌症登月計畫的一重要部分)，利用分子醫學研究中心已建置成熟的多體學(multi-omics)分析技術平台，系統性深入研究國人口腔癌(病患癌組織與癌旁非腫瘤組織)的基因體(全外顯子體及RNA定序)、蛋白體(定量蛋白體及磷酸化蛋白體)與代謝體(定量代謝體)全貌及其相關變異，透過整合性體學大數據分析以瞭解基因體變異所造成的蛋白體/代謝體變化，希望建構首個口腔癌 “多體學藍圖”(基因體→蛋白體→代謝體)，提供探索這些系統性變異對口腔癌發生進展的生物意義；同時結合標靶基因/蛋白質/代謝物定量技術及人源化腫瘤動物模式，研發可應用於作為早期偵測之生物標記與精準醫療用藥標靶或指引。
(2)利用先進蛋白質體學分析技術研發可臨床應用之癌症生物標記
癌症為人類主要死因之一。大部份癌症被診斷時皆為晚期，是癌症死亡率居高不下的主因。除了養成健康生活習慣外，早期診斷與有效治療是目前對抗癌症的唯一有效方法。雖然有效的癌症生物標記(biomarker)並不多，抽取體液(血液、尿液、唾液等)檢查其中可能的癌症生物標記仍是最方便的初步篩檢方法。因此，找尋新穎且更為有效的體液生物標記是對早期診斷癌症非常重要的課題。以質譜學為基礎之蛋白質體學為近年來新興學門，由於具備高靈敏度、高精確度與高通量之特性，被學界寄予厚望可以用來系統性分析(包括定性與定量)癌症相關樣本中蛋白質，藉以找尋與驗證具高應用價值的癌症生物標記。
本實驗室與本校多位同仁合作，共同建立長庚大學蛋白質體學核心實驗室，發展多種蛋白質體相關定性與定量分析技術平台，分別利用三種生物材料(癌症病患組織、體液及癌細胞株)找尋癌症生物標記及分析癌症之異常分子調節機轉。本實驗室目前針對國人數種好發癌症，包括口腔癌、大腸癌、肝癌及胰臟癌同步進行研究，長期目標在於發展出可實際應用於臨床偵測早期癌症及其復發的體液生物標記，同時發展可快速方便檢驗這些生物標記的方法。
目前口腔癌唾液生物標記的主要研究成果已於2016/10發表，領先其他國際團隊，已獲多國專利，並技術移轉給本土新創生技公司，進行後續免疫檢測試劑開發(ELISA及試紙型快篩)與臨床試驗，此產學合作成果亦獲得生技相關獎項的肯定，包括 「2019臺北生技獎-技轉合作獎項優等獎」(2019/07)、「108年度科技部法人鏈結產學合作成果績優案源獎第一名」(2019/11)、 「國研院研發服務平台亮點成果獎」(2021/08) 及合作新創生技公司獲「第16屆國家新創獎-初創企業獎」(2019/12)。該ELISA試劑組已於2020/12/04完成歐盟註冊 (註冊號00159706)，產品已可以進入歐盟銷售。此為國人自行成功開發的第一個口腔癌生物標記免疫檢測商品化試劑組，可為後續一系列衍生或相關檢測產品重要參考品，具指標性意義，對提升防治國人口腔癌的檢測能力預期將有重大影響。而胰臟癌血液生物標記的主要研究成果也已於2011/05發表，亦獲多國專利及技術移轉給本土新創生技公司，進行後續免疫檢測試劑開發與臨床試驗。
(3)研發重要醫用或研究用蛋白質的核酸適體(Aptamer)
核酸適體(Aptamer)是具有獨特立體結構的單鏈RNA或DNA(長度在20～80個鹼基)、可與特定分子標靶以構型互補模式結合，此結合作用與抗體--抗原反應類似，因此核酸適體具有發展成為與抗體類似的拮抗劑或分子靶向工具的高應用潛能。本實驗室已建立以PCR為基礎的核酸適體的高效篩選技術SELEX（systematic evolution of ligands by exponential enrichment），將針對重要醫用或研究用蛋白質開發高親和力核酸適體，提供研發疾病檢測或標靶治療的新穎分子工具。
(4)應用蛋白質體學技術研究細胞訊息傳遞分子機制
本實驗室以累積多年之蛋白質酵素分離純化鑑定經驗，過去十多年中投入並成功研發以質譜學為基礎之多種蛋白質體相關定性與定量分析技術。利用這些強大效能蛋白質體分析工具，我們可以重新擴大研究檢視各種細胞內關鍵訊息傳導路徑、發現新穎蛋白質交互作用及分析各種蛋白質後轉譯修飾作用，這些可能性大幅提升了細胞生物學領域研究的廣度與深度。
Research interests:
The research interests in my lab are to apply multi-omics approaches (genomics, transcriptomics, proteomics and metabolomics) to explore cancer biomarkers for early detection and to investigate novel cellular signaling networks in cell/cancer biology. Specific topics include:
(1) Multiomic analysis of oral squamous cell carcinoma (OSCC). OSCC is a common cancer worldwide that represents a serious and growing problem in many parts of the globe, including Taiwan. However, little improvement has been made for the early detection and targeted therapy of OSCC in the past decades. Our lab leads the Molecular Medicine Research Center (MMRC) OSCC research team to participate in the International Cancer Proteogenome Consortium (ICPC), which is a part of international Cancer Moonshot program led by National Cancer Institute, USA. We apply the multi-omics approach to systemically analyze OSCC specimens (cancer tissues and adjacent non-tumor parts) using genomics (WES and Rseq), proteomics/phosphoproteomics, and metabolomics technology platform established in the MMRC, Chang Gung University. We hope to establish the first Taiwanese OSCC multi-omics blueprint which can greatly facilitate the discovery of new biology of OSCC, as well as the identification new biomarkers and/or therapeutic targets for early detection and effective treatment of OSCC.
(2) R & D of clinically applicable cancer biomarkers. Cancer is one of the major death cause in the world, and delayed diagnosis of cancer represents the main reason of high mortality rate of many cancer types. We put efforts to discover cancer biomarkers from tissues, body fluids and cell lines and their verification in clinical specimens using proteomics technology platforms established in the Chang Gung University Proteomics Core Lab. We focus on four cancer types: OSCC, colorectal, pancreatic and liver cancers. Our long-term goal is to develop clinically useful biomarkers for early detection of cancer, which are expected to significantly improve human health (better patient outcome and less treatment cost). Currently, the major research outcomes for OSCC salivary biomarkers have been published in 2016/10 and 2020/8, respectively, from which a patent for OSCC detection method has been approved by several countries and transferred to a local biotech company for subsequent development of commercial assays (ELISA and rapid test). The product “Immuno-based Rapid Test for Detecting the Oral Cancer Biomarker-OCBM-1” derived from this Industry-university collaboration effort has been awarded the “2019 Taipei Biotech Awards – Technology Transfer Special Mention Award”. The OCBM-1 ELISA kit has obtained European CE marking (registration No. 00159706) on 2020/12, representing the first commercial ELISA kit invented from Taiwan for detecting oral cancer biomarker using saliva specimens. Additionally, the major research outcome for pancreatic cancer blood biomarker has been published in 2011/05, from which a patent for pancreatic cancer detection method has been approved by several countries and transferred to a local biotech company for subsequent development of commercial assays.
(3) Development of aptamer for medically important proteins. Aptamer is a kind of single chain RNA or DNA with unique 3D structure that can selectively bind to a specific target (proteins, peptides, carbohydrates, small molecules, toxins, and even live cells). Aptamer can be produced using an in vitro, PCR-based selection method called SELEX (systematic evolution of ligands by exponential enrichment), displaying high potential as a molecular tool for medically important targets. Our lab has established a high throughput SELEX platform for selecting DNA aptamers against different proteins. We focus on proteins with important clinical relevance or research utility, such as virus protein, snake venom protein, cancer biomarker, etc