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交通大學-生物科技學院

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研究發展

生醫工程研究室    林志生博士(Biomedical Engineering Lab – PI: Dr. Chih-Sheng Lin )

  • 探討心血管疾病中心臟組織之纖維化病變的分子調控機制 
    細胞外基質(extracellular matrix, ECM)的代謝調節失序是許多心血管主要的病理機轉與病變特徵。基質金屬蛋白?(matrix metalloproteinase, MMPs)是一群可降解組織中ECM蛋白質的分解酵素,而基質金屬蛋白?組織抑制因子(tissue inhibitors of MMPs, TIMPs)則為MMPs內源性抑制因子,其精密調控著MMPs的活性。儘管影響ECM的代謝與疾病發生關係密切,但MMPs、TIMPs與心臟組織結構性重塑(remodeling)病程的發生機制至今仍未解。本實驗室利用心臟衰竭(heart failure)與心房顫動(atrial fibrillation)的動物模式來探討ECM、MMPs、TIMPs及其相關因子於心臟重塑病程的交互影響網絡。據此將有助於了解此複雜心血管疾病的致病機轉,進而能研發出新穎且有效性的MMPs抑制藥物,以及應用於心血管疾病的預防與治療。
  • 發展臨床與食品病原體檢測用之生物感測系統 
    近年來生物感測器技術急遽發展,其中包括利用生物感測器來偵測人體感染與食物污染之病原體,而本實驗室已發展可用於登革熱病毒與大腸桿菌O157:H7的生物感測系統。我們利用網版印刷碳電極(screen-printing carbon electrode, SPCE)結合金奈米粒子(gold nanoparticles, AuNPs)加以修飾,經由此技術可大幅提昇SPCE系統的檢測敏感度與偵測極限。 
  • 利用微藻技術進行二氧化碳的減量與生產生質柴油 
    微藻(microalgae)是行光合作用高效能之生物,它們有效率地利用陽光,將水與CO2轉換成生質能(biomass),而某些微藻可合成高量油脂,其可用來轉脂化成為生質柴油(biodiesel)。此外,微藻於培養過程中可大量消耗工廠所排放廢氣中的CO2,以達減碳之效益。本實驗室在本項研究中主要的目的是設計光生物反應器(photobioreactor),並利用微藻技術進行CO2減量與生質柴油生產之研究。

臨床生化工程研究室    毛仁淡博士(Clinical-Biochemical Engineering Lab – PI: Dr. Jen-Tan Mao)

  • Functional role of Haptoglobin in Atherosclerosis 
      Haptoglobin (Hp) is an acute-phase protein, with its plasma levels increasing consistently in response to infection and inflammation. Due to the existence of two different alleles (Hp1 and Hp2) in chromosome 16q22, three main Hp phenotypes exist: Hp1-1, Hp2-1 and Hp2-2. Apparently, the structural difference among the Hp types may drastically affect its biological function and clinical outcomes. So far, we have developed Hemoglobin affinity and monoclonal antibody affinity columns for purifying Hp from human plasma as reported in Protein Expression and Purification and Journal of Chromatography B, respectively. In our previous results, Hp was found to possess an extremely potent antioxidant activity (5 times greater than that of probucol, a well-known potent antioxidant), this finding was a critical milestone in currently related areas and has been published in Proteomics in 2004. Of remarkable interest, the antioxidant activity of the Hp β subunit was extremely potent and markedly greater than probucol (15X). Using a recombinant Hp, we demonstrate that the Hp β chain is an extremely potent antioxidant directly preventing LDL from oxidation as published in Protein Expression and Purification, 2007. It is conceivable that expressed β subunit may provide as an initial utility for the future design of “mini-Hp” for a potent antioxidant. In the clinical study, we established an ELISA assay to determine the phenotypes of Hp in plasma and the pure Hp 1-1, 2-1, and 2-2 were used as standards (Clinical Biochemistry in 2007). By collaborating with the Cardiology Division of Veterans General Hospital at Taipei, 1,200 subjects have been investigated to study whether or not Hp phenotype is associated with the risk in incident coronary artery disease (CAD). Using stepwise logistic regression analyses with the plasma apoA-I levels adjusted to determine the major risk factors, our data suggested that Hp 1-1 was associated with the risk of CAD by 2 times greater than Hp 2-1 and 2-2. Moreover, we are excited by finding the existence of a point deletion in Hp allele 1 mRNA present in all phenotypes of human samples. The deletion mutation resulted in the formation of a stop codon. To our best of knowledge, the existence of this truncated mRNA has never been reported and the critical report is almost done and ready to submit. 
  • Physiological role of milk β-lactoglobulin 
     β-Lactoglobulin (LG) is one of the major milk whey proteins, containing about 10% of the total protein by weight. The molecular mass of LG is 18.5 kDa belonging to the lipocalin family. The secondary structure, it consists of nine β strands and one alpha-helix. The central hydrophobic pocket (calyx) possesses the property of binding to vitamin D, vitamin A, and fatty acids. LG is quite sensitive to thermal denaturation; the secondary structure is altered upon the heating with a transition temperature at 70-80°C. In the last five and half years, we have constructed a detailed thermal denaturation curve for LG with its time and temperature, the data providing the dairy industry with a valuable reference (Journal of Dairy Science, 2005). We have also mapped out a specific amino acid sequence region that is responsible for the thermal change above 80 °C. Such changes also result in losing its ligand binding abilities (retinol and palmitic acid) (Journal of Biological Chemistry, 2004). In addition, we have reported that a monoclonal antibody can only recognize the native form of LG, so that the un-denatured LG content in the processed milk can be determined (Journal of Dairy Science, 2004 and 2006). We showed that LG is a mild antioxidant whose potency is less than that of vitamin E and probucol (the latter being an antioxidant used for clinical therapy). The conversion of the LG monomer to dimer was responsible, in part, for the mode of action in protecting low-density lipoproteins against copper-induced oxidation (Journal of Dairy Science, 2007). More recently, we have shown that LG dramatically stimulates the proliferation of hybridoma B cells, but thermal denaturation abolishes this ability of LG. It is an important observation that the LG receptor was identified as a membrane Ig M using mass spectrum. We identified first the second vitamin D binding site of LG using synchrotron X-ray in National Synchrotron Radiation Research Center (NSRRC) (PROTEINS: Structure, Function, and Bioinformatics, 2008). 
  • Mechanism involved in instant browning reaction over post-harvested fruit 
     Plant polyphenol oxidase (PPO), also known as tyrosinase in animals (EC 1.14.18.1), is an enzyme containing copper that catalyzes two different reactions using molecular oxygen, hydroxylation of monophenols to o-diphenols and oxidation of the o-diphenols to o-quinones. This enzyme, responsible for melanization in animals and for browning in fruits and vegetables, is widely distributed in microorganisms, animals, and plants. We developed a rapid gel-electrophoretic blotting technique to identify the possible molecular form of PPO on a dried chromatographic paper that was immobilized with a colorimetric substrate catechol (Journal of Chromatography B, 2007). The method also allows us to identify potentially potent inhibitors from natural products. Furthermore, in view of recent studies indicating that tyrosinase is responsible for hyperpigmentation in humans, tyrosinase inhibitors have become increasingly important in medical and cosmetic products. We show the presence of a potent volatile inhibitor(s) for PPO in litchi pericarp. The surface of post-harvesting litchi pericarp revealed an opening ultra structure under the scanning electron macroscopic examination, therefore allowing an instant evaporation of PPO inhibitor. As such, the PPO oxidation was proceeded. The novel finding clarifies the mechanism involved in the rapid browning phenomenon of post-harvesting litchi pericarp.


     

計算生物研究室   黃鎮剛博士 (Bio-computational Lab – PI: Dr. Jenn-Kang Hwang)

  •  CELLO-- protein subcellular localization predictor

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  •  pKNOT -- the first knotted protein server

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智慧型計算實驗室    何信瑩博士 (Intelligent Computing Lab – PI: Dr. Shinn-Ying Ho)

  • We aim to develop various evolutionary computation algorithms and optimization methodologies, and provide user-friendly tools for system optimization. A representative paper is as follows: S.-Y. Ho*, L.-S. Shu and J.-H. Chen, "Intelligent Evolutionary Algorithms for Large Parameter Optimization Problems," IEEE Trans. Evolutionary Computation, vol. 8, no. 6, pp. 522-541, Dec. 2004. (Highly cited article) 
  •  Based on the expertise of intelligent computation, we develop various bio-inspired optimization algorithms for computational proteomics, computational systems biology, computational biology, bioinformatics, etc. 
  • We establish national/international interdisciplinary collaboration with biologists to investigate systems biology and validate our proposed models. 
  • We are interested in establishing a user-friendly system of computer-aid vaccine design.
     

酵素與蛋白質研究    楊裕雄博士(Enzyme and Protein Engineering Lab – PI: Dr. Yuh-Shyong Yang)

  • 楊裕雄教授的研究興趣著重於生物科技跨領域研究,包含酵素反應機制、蛋白質工程、基因工程與生物電子等相關領域。近幾年在生物感測電子方面積極開發新的感測元件,希望從生物角度出發為生物電子領域帶來新的發展。實驗室核心技術為酵素與抗體之製備、固定化及特性分析,並應用定點突變與生物資訊進行蛋白質工程以創造特有的酵素性質,進而開發及設計新穎的生物檢驗相關技術,尤其是應用半導體感測器及積體電路作為生物訊號之感測及處理方式,以建構一獨立或可攜式之生物感測系統。

應用微生物與生化研究    曾慶平博士(Applied Microbiology & Biochemistry Lab – PI: Dr. Ching-Ping Tseng)

  • 曾慶平教授致力於以生物技術去除空氣污染之相關研究,成果卓越多次獲得國科會獎項,並入選國科會2008年4月份月曆封面。

      以固定化菌體反應器處理養殖場廢氣

      交通大學生物科技系曾慶平教授及其團隊,由活性污泥中篩選出有效除臭菌株,並設計一套密閉循環之生物反應系統,可取代傳統堆肥場及養殖場用大量木屑或水洗塔來除臭,不但提高除臭效率也減少二次污染,除臭過程乾淨且環保。

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生物藥學與無機化學分析研究室    張正博士(Bioinorganic & Bioanalytical Chemistry Lab – PI: Dr. Cheng Chang)

  • 108+篇國內外重要SCI學術期刊論文(h-Index = 26,累計SCI論文總點數>320點,總被引用次數>2040次)、138+篇科技會議論文及摘要、60篇工業研究報告、130個以上受邀學術演;6+件專利申請及文件(美、中、台)。曾研發三種磁振造影劑(ProHance®、Omniscan®、Teslascan®:2000世界市場值約一億美元);4個IND及2個NDA新藥申請(美、歐)。財團法人傑出人才發展基金會「傑出人才講座」獎(1995-2000)、Asia Pacific Society of Bioscientists 2nd International Symposium & Workshop Excellence Award(Hong Kong,1996)。 

    最常被引用之論文 (> 80 次):
    1. C.A. Chang*, H.G. Brittain, J. Telser, and M.F. Tweedle. "pH Dependence of Relaxivities and Hydration Numbers of Gadolinium(III) Complexes of Linear Aminocarboxylates", Inorg. Chem., 1990, 29, 4468-4473. [SCI: 4.123; Rank: 4/43; No. of Citations: 84 ]
    2. M.F. Tweedle, J.J. Hagan, S. Mantha, K. Kumar, and C.A. Chang. "Reaction of Gadolinium Chelates with Endogenously Available Ions", Mag. Reson. Imaging, 1991, 9, 409-415. [SCI: 1.486; Rank: 47/87; No. of Citations: 85 ]
    3. K. Kumar, C.A. Chang, and M.F. Tweedle. "Equilibrium and Kinetic Studies of Lanthanide Complexes of Macrocyclic Polyaminocarboxylates", Inorg. Chem., 1993, 32, 587-593. [SCI: 4.123; Rank: 4/43; No. of Citations: 102 ]
    4. C.A. Chang*, L. Francesconi, M.F. Tweedle, et. al. "Metal Complexes for Magnetic Resonance Imaging: Synthesis and Characterizations of Fe(DO3A), Na[Fe(DOTA)], Gd(DO3A), and Na[Gd(DOTA)]", Inorg. Chem., 1993, 32, 3501-3508. [SCI: 4.123; Rank: 4/43; No. of Citations: 150 ]
    5. C.A. Chang*, L.Francesconi, D. Dischino, M. Malley, J. Gougoutas, and M.F. Tweedle. "Synthesis, Stability, and Structures of Gd(III) and Y(III) Macrocyclic Polyaminocarboxylates". Inorg. Chem., 1994, 33, 3567-3575. [SCI: 4.123; Rank: 4/43; No. of Citations: 130 ]
     

藥物設計與系統生物實驗室    楊進木博士BioXGEM – PI: Dr. Jinn-Moon Yang )

  • 我的研究以電腦輔助藥物設計(Computer-aided drug design)及結構生物資訊(Structural bioinformatics)為主軸。在電腦輔助藥物設計方面,目前我們是分子對接(Molecular docking)軟體(GEMDOCK)提供者之一,我們也與國內外超過十個實驗室合作,經由生物實驗證實我們的方法確實可找到藥物標的(如Envelop protein、Skimate kinase、 influenza virus neuraminidase)前導藥物(Lead compound)、功能催化部位(如ß-lactoglobulin)、及蛋白質功能設計(如endo-chitosanase to exo-chitosanase)等,這些成果已發表多篇論文在這些領域最好的期刊上。這些論文從2004年起被引用次數已超過70次 (根據ISI);另外GEMDOCK被國內外數十個實驗室使用,除研究的應用外,此軟體也使用在教學上。這些成果讓我們獲得2007年國家新創獎(由國家生技醫療產業策進會主辦),是唯一以電腦軟體獲獎的團體。

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  • 在結構生物資訊方面,我們在蛋白質結構預測(PS2)、高速蛋白質結構的搜尋與應用(3D-BLAST)、及結構為基的蛋白質網路(3D-partner)已有相當成果,這些研究已發表在相關領域最好的期刊上(如Nucleic Acids Research、Genome Biology) 。最值得一提的研究成果是3D-BLAST,3D-BLAST搜尋蛋白質結構的速度與BLAST搜尋胺基酸序列一樣快,同時具備BLAST的優點與操作介面,也就是能提供可信的統計基礎(e-value)及高效率的搜尋能力。因此3D-BLAST可能成為蛋白質結構搜尋的標準,對於結構搜尋有巨大影響,此研究成果已引起相關學者的重視與討論。2007年起這些論文被引用次數已超過13次,目前已有44個國家,超過5,100 人次使用我們提供的服務。

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心臟電氣學及心血管生物資訊學實驗室     楊騰芳博士
(Electrocardiology and Cardiovascular Bioinformatics Lab – PI: Dr. Ten-Fang Yang)

 

  • 平均訊號心電圖,時域領域及頻率領域之信號分析研究。 
  •  心率變異性,時域領域及頻率領域之信號分析研究。
  • 血液透析腎衰竭病患之平均訊號心電圖之研究。 
  •  血液透析腎衰竭病患之心率變異性之研究。 
  •  平均訊號心電圖,性別、年齡、種族差異之研究。 
  •  心率變異性,性別、年齡、種族差異之研究。 
  •  正常台灣人之平均訊號心電圖研究。 
  •  正常台灣人之心率變異性研究。 
  •  心臟猝死之病因及心臟電氣學偵測方式之研究。 
  •  標準12導程心電圖在心臟學之研究。 
  •  向量心電圖在心臟電氣學之研究。 
  •  平均訊號心電圖模式分析研究。

 研究室    王雲銘博士 ( Lab – PI: Dr. Yun-Ming Wang)

  • 2007 Joint Annual Meeting ISMRM (International Society for Magnetic Resonance in Medicine)-ESMRMB (European Society for Magnetic Resonance in Medicine and Biology) 2007 Poster Award 3rd place

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  • Synthesis, Complexation and Water Exchange Properties of Gd(III)–TTDA–Mono and Bis(amide) Derivatives and Their Binding Affinity to Human Serum Albumin, Dalton Trans., 2749-2759, 2007. (Selected as Journal Cover)
    我們成功的合成出一個單醯胺TTDA衍生物,TTDA-N-MOBA及兩個雙醯胺TTDA衍生物,TTDA-BMA與TTDA-BBA。TTDA-N-MOBA、TTDA-BMA及TTDA-BBA之釓金屬錯合物在20 MHz、37 C下,求得其弛緩率(r¬1)分別為4.23、3.92及4.41 mM1 s1。釓金屬錯合物之內層水分子交換速率(kex298)及分子轉動相關時間(R)則利用9.4 T之17O NMR求得。實驗結果顯示TTDA單醯胺衍生物,[Gd(TTDA-MOBA)],其kex298值為29.1  106 s1,大約是[Gd(TTDA)]2−之kex298值的1/5。另一方面,TTDA雙醯胺衍生物,[Gd(TTDA-BMA)]與[Gd(TTDA-BBA)],其kex298值分別為15.2  106 s1及15.6  106 s1,大約是[Gd(TTDA)]2−之kex298值的1/10。另外,由17O NMR實驗結果顯示, [Gd(TTDA-MOBA)]、[Gd(TTDA-BMA)]及[Gd(TTDA-BBA)]之分子轉動相關時間分別為157、119及187 ps,其值高於[Gd(DTPA)]2(103 ps)與[Gd(TTDA)]2−(104 ps)。在 [Gd(TTDA-BBA)]與HSA形成非共價性鍵結實驗中,分別求得鍵結常數(KA)為1.0  104 M1,而鍵結弛緩率( )分別為52.0 mM1 s1。最後,由弛緩率研究與超過濾實驗發現,[Gd(TTDA-BBA)]與HSA之鍵結弛緩率高於商業化之磁振造影對比劑MS-325。
  • Synthesis and Characterization of a New Bio-activated Paramagnetic Gadolinium(III) Complex [Gd(DOTA-FPG)(H2O)] for Tracing Gene Expression, Bioconjugate Chem. 18, 1716-1727, 2007. (Selected as Journal cover)
    我們設計、合成出具有半乳喃醣官能基之新穎釓金屬錯合物 [Gd(DOTA-FPG)],並針對其物、化性及生物活性上做一系列之探討。利用 17O NMR 測定Dy(III)金屬離子誘導水中17O 核種之化學位移變化來測得 [Gd(DOTA-FPG)]之內層水分子數,得其內層水分子數q = 0.92,並利用 Eu(III)金屬錯合物的化學發光性質以螢光光譜儀測得之數值求得其內層水 分子數q = 1.08,由這兩個實驗結果來確定其內層水分子數。另外我們再以 17O 核磁共振光譜儀實驗來求得釓金屬錯合物之弛緩率(1/ T1、1/ T2)以及化學位移(ω),再進行數據逼近,可計算出釓金屬錯合物之內層水分子停留時間(τM)及分子轉動相關時間(τR)。弛緩率( r1 )主要受到內層水交換速率( kex298 )及分子轉動相關時間(τR)影響,在17O-NMR 研究結果顯示[Gd(DOTA-FPG)]之水交換速率kex298 近似於[Gd(DOTA)]− 及[Gd(DTPA)]2− , 明顯較[Gd(TRITA-bz-NO2)]− 及[Gd(TTDA)]2− 來的低, 實驗結果亦發現將[Gd(DOTA)]−的一個羧酸基置換成雙氟甲苯基半乳喃糖使得分子轉動相關時間增加。

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  • 由弛緩率的增加和磁振照影影像對比提高之證據說明了當[Gd(DOTA-FPG)]在有半乳喃醣酵素和人類血清蛋白(HSA, human serum albumin)表現的環境時,半乳喃醣酵素(β-gal)或人類血清蛋白(HSA)與切除了半乳喃醣官能基部分的釓金屬錯合物產生了共價性鍵結,相對增加了分子轉動相關時間(τR)而使得弛緩率提高。在體內動物影像研究方面,具有半乳糖酵素基因表現之CT26(老鼠結腸癌細胞)/ β-gal 腫瘤在磁振造影影像中較CT26 腫瘤具有較高的訊號增強效果。因此,[Gd(DOTA-FPG)(H2O)] 為具有生物活性之磁振造影對比劑且有足夠的潛力追蹤基因表現。 

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生物資訊演算法實驗室   盧錦隆博士 (Bioinformatics Algorithm Lab– PI: Dr. Chin Lung Lu)

  • \Multiple Sequence Alignment with Constraints  (MuSiC, MuSiC-ME, RE-MuSiC) 
    We are the first to propose the concept of constrained sequence alignment that allows biologists to incorporate their knowledge about structures/functionalities/consensuses of their datasets into sequence alignment. By specifying known functionally, structurally or evolutionarily related residues/nucleotides of the input sequences as constraints, the output of the constrained sequence alignment is an optimal sequence alignment in the condition that the user-specified residues/nucleotides should be aligned together in the alignment, so that the output alignment can more accurately reflect the true biological relationships among the input sequences. In this study, we have first designed an efficient algorithm for computing a constrained alignment of multiple sequences and have also developed a web server, called MuSiC (Multiple Sequence alignment with Constraints), for the online analysis. Using MuSiC, we have successfully located the subsequence fragment of the RNA sequence of SARS that is capable of folding itself into a stable RNA secondary structure with pseudoknot responsible for the replication of SARS viruses (Bioinformatics, 20:2309-2311, 2004). Then we have further developed its memory-efficient version, called MuSiC-ME (Memory-Efficient Multiple Sequence alignment with Constraints), that allows the users to align multiple sequences of length up to several thousand residues (Bioinformatics, 21:20-30, 2005). More recently, we have developed RE-MuSiC by further enhancing the constraint formulation of MuSiC as regular expressions, which is convenient in expressing many biologically significant patterns like those collected in the PROSITE database, or structural consensuses that often involve variable ranges between conserved parts. Experiments demonstrate that RE-MuSiC can be used to help predict important residues and locate evolutionarily conserved structural elements (Nucleic Acids Research, 35:W639-644, 2007).

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Figure 1: Three GST (Glutathione S-Transferase) proteins: The structural similarity between these three proteins is very high, but their pairwise sequence identities are extremely low.

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Figure 2: The constrained sequence alignment produced by RE-MuSiC, using the pattern of "[ST]-x(2)-[DE]" as the constraint, in which the residues shaded in yellow match the pattern. In addition, the residues in green boxes that correspond to the active sites shared by these three GST proteins are aligned together.

生化及物理化學研究室    林苕吟博士(Resaerch and Application of Biological Macromolecules Lab – PI: Dr. Tiao-Yin Lin)

  • 氨基酸突變對thioredoxin reductase催化之電子傳遞的影響

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分子調控研究室    彭慧玲博士(Molecular regulation Lab – PI: Dr. Hwei-Ling Peng)

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生物有機與分子演化研究室    吳東昆博士(Bioorganic and Molecular Evolution Lab – PI: Dr. Tung-Kung Wu)

  • The structure-function-mechanism and molecular evolution studies of oxidosqualene cyclase enzymes: Our goals in this project are to gain in-depth insights of how cyclase enzymes catalyze the complex cyclization/rearrangement reactions during sterol and triterpene biosynthesis that have captivated chemists and biochemists for more than half a century, and to develop novel inhibitors of these enzymes for potential use as antifungal, hypocholesterolemic, and phytotoxic agents. In parallel, promiscuous residues of cyclase enzymes is subjected to protein engineering to study product specificity/diversity during the molecular evolutionary course of the cyclases. We have identified several important amino acid residues involved in the enzyme catalysis and substrate binding. Numerous truncated intermediates have also been isolated to directly demonstrate the function of the amino acids to the mechanism of the oxidosqualene cyclization/rearrangement cascade.

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  • The Research on the biosolar energy device design and biomass-directed renewable energy production: Our goals here are to use materials from organic, organometallic, nano-particles, and bio-molecules and integrate them into a biosensitized solar cell device for the conversion of solar energy into electric or chemical energy. Specifically, protein will be subjected to protein engineering to obtain mutants with altered or improved electron transfer activity and tested for biosolar energy conversion efficiency. In parallel, results from the ultrafast relaxation dynamics showed profound effects of the protein matrix on the prosthetic group in different environments. We have successfully demonstrated the first example of biosensitized solar cell made with artificial proteins as potential photosensitizers and opened up a new avenue for the design and development of new biosensors, photo-electrocatalysts, or bio-mimetic solar cells.

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分子遺傳研究    楊昀良博士(Molecular Genetics Lab – PI: Dr. JYun-Liang Yan)

  • 發現白色念珠菌形態/毒性因子與抗藥因子有協同調控及交互作用。兩個途徑(Pathways)都受已知的毒性因子Efg1 與Cph1的調控。 
  • 發現第一個抗登革熱病毒的藥物。

生物晶片與細胞生物研究室    袁俊傑博士(The Cell Biology and BioChip Lab – PI: Dr. Chiun-Jye Yuan)

  • Mst3所引發細胞凋亡之分子機轉之研究
    在近期研究中我們發現Mst3 不只存在於細胞質內,亦存在於粒線體膜間隙(intermembrane space) 內。我們更進一步發現在粒線體膜間隙Mst3會與其中之誘發細胞凋亡蛋白,如 AIF 及 endonuclease G (EndoG),結合形成複合體。而經由免疫金粒子電子顯微影像及西方墨點法進一步確認Mst3 存在於粒線體膜間隙的事實。在粒線體中,Mst3可能參與了調控誘發細胞凋亡蛋白(如 AIF 及 EndoG)的活性。然而,Mst3亦有可能激活附著於複合體上的未知的核酸內切酵素(DNase),而促成細胞凋亡。

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圖一、Mst3在粒線體內與 AIF 及 endonuclease G (EndoG)形成複合體。圖中所示,細胞內Mst3 (絲線狀綠色螢光) 與 Mitotracker (專一性粒線體標記、紅色螢光)、AIF 及 EndoG (皆為紅色螢光)有重疊現象,即在螢光顯微影像呈黃菊色訊號。

  • Mst3 在孕婦生產過程及懷孕期病變上角色之探討
    由病理切片(圖二)及細胞作用機轉相關研究顯示, Mst3 在孕婦懷孕後期會受到氧化逆境(oxidative stress)的刺激 (而非生產過程相關荷爾蒙,如、前列腺素 E1、摧產素、血管收縮素等) 在胎盤中大量表現活化,並進而激發胎盤內滋養細胞(trophoblasts)的凋亡現象。此一現象可能是促發胎兒生產的起始信號,並對生產後期的協助胎盤剝離子宮內膜有實際助益。 

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圖二、人類自然產胎盤(a-d)、 剖腹產胎盤 (e-h)及產程第一期胎兒組織 (fetal membrane of first trimester) (i-l)。 Mst3 表現 (a,e,i)、細胞凋亡s (b,f,j)、 nitrotyrosine訊號s (c,g,k)及aspase3活化 (d,h,l)。

  • 研發奈米生物材料並應用於癌症治療
    我們已開發一新穎的包裹山葵過氧化酵素的奈米粒子(horseradish peroxidase -encapsulated silica nanoparticles; HRP-SNP)。此一奈米粒子的平均大小約為直徑 100 nm (圖 3)。 實驗證實HRP-SNP 可有效將無毒前驅藥indole-3-acetic acid (IAA)摧化成有毒之抗癌藥,並可應用於癌細胞的毒殺。進一步實驗證實HRP-SNP 生物相容性高,對細胞並不具毒性,且因外源性蛋白被玻璃凝膠基質所保護,而具減少免疫反應及延長酵素活性及穩定性的優勢。 

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圖三、TEM of the developed ESNP.


分子生物物理研究室    張家靖博士(Nano-Biotechnolgy Lab – PI: Dr. Chia-Ching Chang)

  • Self-assembled molecular magnets on patterned silicon substrates: Bridging bio-molecules with nanoelectronics 
    The paper reports the methods of preparing molecular magnets and patterning of the molecules on a semiconductor surface. A highly magnetically aligned metallothionein containing Mn and Cd (Mn,Cd-MT-2) is first synthesized, and the molecules are then placed into nanopores prepared on silicon (0 0 1) surfaces using electron beam lithography and reactive ion-etching techniques. We have observed the self-assemble growth of the MT molecules on the patterned Si surface such that the MT molecules have grown into rod or ring type three dimensional nanostructures, depending on the patterned nanostructures on the surface. We also provide scanning electron microscopy, atomic force microscopy, and magnetic force microscope studies of the molecular nanostructures. This engineered molecule shows molecular magnetization and is biocompatible with conventional semiconductors. These features make Mn,Cd-MT-2 a good candidate for biological applications and sensing sources of new nanodevices. Using molecular self-assembly and topographical patterning of the semiconductor substrate, we can close the gap between bio-molecules and nanoelectronics built into the semiconductor chip.

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  • Laser induced popcornlike conformational transition of nanodiamond as a nanoknife 
    Nanodiamond (ND) is surrounded by layers of graphite on its surface. This unique structure feature creates unusual fluorescence spectra, which can be used as an indicator to monitor its surface modification. Meanwhile, the impurity, nitroso (C-N=O) inside the ND can be photolyzed by two-photon absorption, releasing NO to facilitate the formation of a sp3 diamond structure in the core of ND and transforming it into a sp2 graphite structure. Such a conformational transition enlarges the size of ND from 8 nm into 90 nm, resulting in a popcorn-like structure. This transition reaction may be useful as nano-knives in biomedical application.

    1. SEM images of the A549 cell lines, irradiated with/without laser following ND treatment.
    2. SEM image of 6 nm nano-diamond before and after laser radiated. The average size of laser radiated nano-diamond is about 90 nm.

 

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整合系統生物學研究室   黃憲達博士 (Integrative Systems Biology Lab – PI: Dr. Hsien-Da Huang)

 

  • [MicroRNA Regulation: Databases and Tools]
    Recent works have demonstrated that microRNAs (miRNAs) are involved in critical biological processes by suppressing the translation of coding genes. In order to facilitate the investigation of microRNA regulation, we developed several biological databases and computational tools in this important field. Six articles in this filed were published in Nucleic Acids Research (2007 SCI Impact = 6.954). miRNAMap was selected as hot research in 2006 NAR Database Issue. miRNAMap was genomics maps for microRNA genes and their targets in metazoan genomes (Nucl Acids Res, 2006, Nucl Acids Res, 2008). ViTa is a database of host microRNA targets on viruses (Nucl Acids Res, 2007). We also survey the literatures to extract the RNA structural motifs and their functions to construct the RegRNA database (Nucl Acids Res, 2006). The RNAMST web server was developed for searching RNA structural homologs (Nucl Acids Res, 2006). RNALogo is designed as a new approach to display structural RNA alignment (Nucl Acids Res, 2008). These databases and tools were cited more than 53 times during last two years.

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  • [Protein Post-translational Modification: Database and Tools]
    Protein Post-Translational Modification (PTM) plays an essential role in cellular control mechanisms that adjust protein physical and chemical properties, folding, conformation, stability and activity, thus also altering protein function. Four articles in this filed were published in Nucleic Acids Research (2007 SCI Impact = 6.954). dbPTM is a comprehensive information repository of protein post-translational modification (PTM) (Nucl Acids Res, 2006). Furthermore, we developed KinasePhos [1.0, 2.0], which is a web tool for identifying protein kinase-specific phosphorylation site (Nucl Acids Res, 2005, 2007, J. Comp Chem 2005). Besides, ProKware was designed as an integrated software for presenting protein structural properties in protein tertiary structures (Nucl Acids Res, 2006). These database and tools were totally cited more than 50 times during last three years.

 

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分子抗癌研究室   趙瑞益博士 (Molecular Anticancer Lab – PI: Dr. Jui-I Chao) 

  • 近幾年我們針對癌細胞中的標靶基因survivin及securin等,進行深入的研究。例如多種人類癌細胞(包括肺癌、乳癌、大腸癌及子宮頸癌等)會大量表達survivin蛋白,但在正常成人細胞不會表達survivin。Survivin蛋白具有抗細胞凋亡及促細胞分裂的功能,調控癌細胞中survivin蛋白的表達,與癌症的發生有密切的關係,而抑制survivin蛋白的表達,也可能應用於治療癌症。我們建立了cyclin B1/cdc2與p38 MAP kinase可分別為正調控及負調控survivin基因及蛋白的表現(Chao et al., 2004, JBC)。此外,利用共軛焦顯微鏡及免疫螢光染色,建立survivin蛋白會大量表達於癌細胞之有絲分裂期,並會聚集於細胞質分裂期的midbody位置(Kuo et al., 2004, JBC)。同時我們發現將survivin基因阻斷,會促進抗癌藥物抑制癌細胞的生長及促細胞凋亡之作用(Chao and Liu, 2006, Mol. Pharmacol.)。以COX-2的抑制劑,celecoxib及etodolac,發現抑制COX-2的活性會降低survivin蛋白表達,並加強抗癌藥物oxaliplatin的抗癌效果(Lin et al., 2005, Biochem. Pharmacol.)。Celecoxib會經由活化p38 MAP kinase路徑,抑制大腸癌細胞中survivin蛋白的表達(Hsiao et al., 2007, TAAP)。而黃芩素(baicalein)會抑制膀胱癌細胞中survivin的表達,並誘發癌細胞凋亡(Chao et al., 2007, Mol. Cancer Ther.)。在抗癌奈米科技(Anticancer Nanotechnology)的研究,我們發現奈米鑽石具有特殊螢光特性及作用,被選為生物物理期刊的封面(Chao et al., 2007, Biophys. J.)。此奈米材質不會造成正常細胞毒性及細胞凋亡,具有高度的生物相容性,並且奈米鑽石在細胞內的螢光強度可被檢測及量化 (Liu et al., 2007, Nanotechnology),我們進一步以蛇毒蛋白連結奈米鑽石,可辨識細胞上的接受器(Liu et al., 2008, Nanotechnology),目前我們已經開發出奈米鑽石攜帶抗癌藥物的方法。此外,我們進一步開發奈米鑽石作為癌細胞及幹細胞的標定、偵測及追蹤等應用。

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生化與遺傳工程研究室    邱顯泰博士(Biochemical and Genetic Engineering Lab – PI: Dr. Hsien-Tai Chiu)

  • 天然藥物生物合成基因群組的遺傳基因選殖、定序分析、酵素功能鑑定,進行藥物研發。
  • 天然物的組合式生物合成,以各種生合成基因或酵素,組合製造出一群具生物活性藥物的衍生物,達生技製藥目的。
  • 為臺灣靈芝聯盟成員,從事藥用真菌靈芝的全基因體解碼,及靈芝多醣體與三?類生合成途徑基因與圖譜建構研究,貢獻於藥用真菌的功能性基體研究及中草藥科學化。
  • 研究致病微生物生合成遺傳基因群組,解析基因並鑑定其酵素功能,結合生物資訊研發致病微生物的抑制藥物,完成致病菌生物資訊與演化分析。
  • 完成新穎酵素的化學與生化機理研究(含受質專一性、立體與幾何選擇性),並設計與成功合成酵素抑制劑、得動力學結果,應用酵素於在有機化學與藥物合成。
  • 幹細胞導向分化與增殖。
  • 應用生物資訊成功預測RNA二級結構與物種基因體演化。

腫瘤免疫治療研究室    廖光文博士(Immunology and Oncology Lab – PI: Dr. Kuang-Wen Liao)

  • 免疫學:已檢驗出幽門螺旋桿菌對於細胞產生影響之主要分子—Hsp-60,正深入探討其誘發免疫反應之主要機制,並研究Hsp60對於其他細胞所產生之影響
  • 微脂體 (Liposome):已完成此構型之建構,深入研究其快速且穩定吸附的作用力之機制及原理,同時利用此微脂體之特性包覆藥物,並結合導向分子
    以達到專一性輸送藥物之目的。
  • 抗體之製作及蛋白質工程:完成以VEGF及IgG Fc部份結合之抗體生產,純化及應用。
    發現其可有效達到治療腫瘤之目的。

計算化學研究室   尤禎祥博士 (Computational Chemistry Lab– PI: Dr. Jen-Shiang Yu)

  • 理論配位化學:以量子化學理論研究過渡金屬配位化合物的多重鍵結性質與反應途徑,及配位化學在金屬蛋白研究上之應用。

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  •  蛋白質結構與反應之理論:利用各種計算化學方法,如全初始化理論(ab initio)、密度泛函理論(density function theory)、半經驗理論(semi-empirical methods)以及分子力學(molecular mechanics)等理論或其混合方法,探討蛋白質構形與相關生化反應的理論性質。

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 演化生物資訊實驗室     林勇欣博士 (Evolutionary Bioinformatics Lab – PI: Dr. Yeong-Shin Lin)

  • Many Saccharomyces cerevisiae duplicate genes that were derived from an ancient whole-genome duplication (WGD) unexpectedly show a small synonymous divergence (K S), a higher sequence similarity to each other than to orthologues in Saccharomyces bayanus, or slow evolution compared with the orthologue in Kluyveromyces waltii, a non-WGD species. This decelerated evolution was attributed to gene conversion between duplicates. Using ≈300 WGD gene pairs in four species and their orthologues in non-WGD species, we show that codon-usage bias and protein-sequence conservation are two important causes for decelerated evolution of duplicate genes, whereas gene conversion is effective only in the presence of strong codon-usage bias or protein-sequence conservation. Furthermore, we find that change in mutation pattern or in tDNA copy number changed codon-usage bias and increased the K S distance between K. waltii and S. cerevisiae. Intriguingly, some proteins showed fast evolution before the radiation of WGD species but little or no sequence divergence between orthologues and paralogues thereafter, indicating that functional conservation after the radiation may also be responsible for decelerated evolution in duplicates.

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Y.-S. Lin, J.K. Byrnes, J.-K. Hwang, and W.-H. Li*. (2006). Codon usage bias versus gene conversion in the evolution of yeast duplicate genes. Proc. Natl. Acad. Sci. USA. 103: 14412-14416.
 

 
認知行為與神經功能研究室    曲在雯博士 (Cognitive Neuroscience Lab – PI: Dr. Tzai-Wen Chiu)
 
聽神經元之與音編碼機制:
 
  • 單一聽神經細胞對聲音之反應特性

以單細胞外記錄法記錄大鼠單一聽神經元對各種不同聲音的感受野,此研究成果可進一步用在預測單一聽神經細胞對於複雜聲之反應特徵。
 

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  • 人類聽覺皮層對聲音編碼之神經生理機制
     
    本實驗室與腦中心、成大生理所及美國愛荷華大學醫學院神經外科共同合作,以侵入式大腦皮層電位(ECoG)錄法探討人類聽覺皮層對聲音反應之特性,以期找出人腦對於語音編碼之神經生理機制。
 

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細胞骨架及型態發生實驗室     黃兆棋博士 (Cytoskeleton and Cellular Morphogenesis Lab – PI: Dr. Eric Hwang)

  • We used pluripotent P19 cells to study the function of microtubule-associated proteins during neuritogenesis. Multi-dimensional protein identification technology (one type of gel-free high throughput proteomics) was performed on microtubule-associated proteins prepared before versus shortly after neurite induction. More than 800 proteins were consistently identified in both proteomes. Surprisingly, when these two proteomes were quantitatively compared, the majority of the proteome remain unchanged. Substantial changes in the microtubule-associated proteome occurred at the level of individual proteins. Based on our proteomic results, we assayed primary neurons using RNA interference to identify a novel inhibitory role for protein TRIM2 in neurite elongation.

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