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交通大学-分子医学与生物工程所

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研究成果

分子遗传研究    杨昀良博士(Molecular Genetics Lab – PI: Dr. Yun-Liang Yan)

  • 发现白色念珠菌形态/毒性因子与抗药因子有协同调控及交互作用。两个途径(Pathways)都受已知的毒性因子Efg1 与Cph1的调控。 
  • 发现第一个抗登革热病毒的药物。

研究室    王云铭博士 ( 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)
    我们成功的合成出一个单醯胺TTDA衍生物,TTDA-N-MOBA及两个双醯胺TTDA衍生物,TTDA-BMA与TTDA-BBA。TTDA-N- MOBA、TTDA-BMA及TTDA-BBA之钆金属错合物在20 MHz、37 C下,求得其弛缓率(r¬1)分别为4.23、3.92及4.41 mM1 s1。钆金属错合物之内层水分子交换速率(kex298)及分子转动相关时间(R)则利用9.4 T之17O NMR求得。实验结果显示TTDA单醯胺衍生物,[Gd(TTDA-MOBA)],其kex298值为29.1  106 s1,大约是[Gd(TTDA)]2−之kex298值的1/5。另一方面,TTDA双醯胺衍生物,[Gd(TTDA-BMA)]与[Gd(TTDA- BBA)],其kex298值分别为15.2  106 s1及15.6  106 s1,大约是[Gd(TTDA)]2−之kex298值的1/10。另外,由17O NMR实验结果显示, [Gd(TTDA-MOBA)]、[Gd(TTDA-BMA)]及[Gd(TTDA-BBA)]之分子转动相关时间分别为157、119及187 ps,其值高于[Gd(DTPA)]2(103 ps)与[Gd(TTDA)]2−(104 ps)。在 [Gd(TTDA-BBA)]与HSA形成非共价性键结实验中,分别求得键结常数(KA)为1.0  104 M1,而键结弛缓率( )分别为52.0 mM1 s1。最后,由弛缓率研究与超过滤实验发现,[Gd(TTDA-BBA)]与HSA之键结弛缓率高于商业化之磁振造影对比剂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)
    我们设计、合成出具有半乳喃醣官能基之新颖钆金属错合物 [Gd(DOTA-FPG)],并针对其物、化性及生物活性上做一系列之探讨。利用 17O NMR 测定Dy(III)金属离子诱导水中17O 核种之化学位移变化来测得 [Gd(DOTA-FPG)]之内层水分子数,得其内层水分子数q = 0.92,并利用 Eu(III)金属错合物的化学发光性质以萤光光谱仪测得之数值求得其内层水 分子数q = 1.08,由这两个实验结果来确定其内层水分子数。另外我们再以 17O 核磁共振光谱仪实验来求得钆金属错合物之弛缓率(1/ T1、1/ T2)以及化学位移(ω),再进行数据逼近,可计算出钆金属错合物之内层水分子停留时间(τM)及分子转动相关时间(τR)。弛缓率( r1 )主要受到内层水交换速率( kex298 )及分子转动相关时间(τR)影响,在17O-NMR 研究结果显示[Gd(DOTA-FPG)]之水交换速率kex298 近似于[Gd(DOTA)]− 及[Gd(DTPA)]2− , 明显较[Gd(TRITA-bz-NO2)]− 及[Gd(TTDA)]2− 来的低, 实验结果亦发现将[Gd(DOTA)]−的一个羧酸基置换成双氟甲苯基半乳喃糖使得分子转动相关时间增加。

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  • 由弛缓率的增加和磁振照影影 像对比提高之证据说明了当[Gd(DOTA-FPG)]在有半乳喃醣酵素和人类血清蛋白(HSA, human serum albumin)表现的环境时,半乳喃醣酵素(β-gal)或人类血清蛋白(HSA)与切除了半乳喃醣官能基部分的钆金属错合物产生了共价性键结,相对增 加了分子转动相关时间(τR)而使得弛缓率提高。在体内动物影像研究方面,具有半乳糖酵素基因表现之CT26(老鼠结肠癌细胞)/ β-gal 肿瘤在磁振造影影像中较CT26 肿瘤具有较高的讯号增强效果。因此,[Gd(DOTA-FPG)(H2O)] 为具有生物活性之磁振造影对比剂且有足够的潜力追踪基因表现。 

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生物芯片与细胞生物研究室    袁俊杰博士(The Cell Biology and BioChip Lab – PI: Dr. Chiun-Jye Yuan)

  • Mst3所引发细胞凋亡之分子机转之研究
    在近期研究中我们发现Mst3 不只存在于细胞质内,亦存在于粒线体膜间隙(intermembrane space) 内。我们更进一步发现在粒线体膜间隙Mst3会与其中之诱发细胞凋亡蛋白,如 AIF 及 endonuclease G (EndoG),结合形成复合体。而经由免疫金粒子电子显微影像及西方墨点法进一步确认Mst3 存在于粒线体膜间隙的事实。在粒线体中,Mst3可能参与了调控诱发细胞凋亡蛋白(如 AIF 及 EndoG)的活性。然而,Mst3亦有可能激活附着于复合体上的未知的核酸内切酵素(DNase),而促成细胞凋亡。

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图一、Mst3在粒线体内与 AIF 及 endonuclease G (EndoG)形成复合体。图中所示,细胞内Mst3 (丝线状绿色萤光) 与 Mitotracker (专一性粒线体标记、红色萤光)、AIF 及 EndoG (皆为红色萤光)有重叠现象,即在萤光显微影像呈黄菊色讯号。

  • Mst3 在孕妇生产过程及怀孕期病变上角色之探讨
    由病理切片(图二)及细胞作用机转相关研究显示, Mst3 在孕妇怀孕后期会受到氧化逆境(oxidative stress)的刺激 (而非生产过程相关荷尔蒙,如、前列腺素 E1、摧产素、血管收缩素等) 在胎盘中大量表现活化,并进而激发胎盘内滋养细胞(trophoblasts)的凋亡现象。此一现象可能是促发胎儿生产的起始信号,并对生产后期的协助胎盘剥离子宫内膜有实际助益。 

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图二、人类自然产胎盘(a-d)、 剖腹产胎盘 (e-h)及产程第一期胎儿组织 (fetal membrane of first trimester) (i-l)。 Mst3 表现 (a,e,i)、细胞凋亡s (b,f,j)、 nitrotyrosine讯号s (c,g,k)及aspase3活化 (d,h,l)。

  • 研发奈米生物材料并应用于癌症治疗
    我们已开发一新颖的包裹山葵过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约为直径 100 nm (图 3)。 实验证实HRP-SNP 可有效将无毒前驱药indole-3-acetic acid (IAA)摧化成有毒之抗癌药,并可应用于癌细胞的毒杀。进一步实验证实HRP-SNP 生物相容性高,对细胞并不具毒性,且因外源性蛋白被玻璃凝胶基质所保护,而具减少免疫反应及延长酵素活性及稳定性的优势。 

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图三、TEM of the developed ESNP.

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

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分子生物物理研究室    张家靖博士(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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分子抗癌研究室   赵瑞益博士 (Molecular Anticancer Lab – PI: Dr. Jui-I Chao) 

  • 近 几年我们针对癌细胞中的标靶基因survivin及securin等,进行深入的研究。例如多种人类癌细胞(包括肺癌、乳癌、大肠癌及子宫颈癌等)会大量 表达survivin蛋白,但在正常成人细胞不会表达survivin。Survivin蛋白具有抗细胞凋亡及促细胞分裂的功能,调控癌细胞中 survivin蛋白的表达,与癌症的发生有密切的关系,而抑制survivin蛋白的表达,也可能应用于治疗癌症。我们建立了cyclin B1/cdc2与p38 MAP kinase可分别为正调控及负调控survivin基因及蛋白的表现(Chao et al., 2004, JBC)。此外,利用共轭焦显微镜及免疫萤光染色,建立survivin蛋白会大量表达于癌细胞之有丝分裂期,并会聚集于细胞质分裂期的midbody位 置(Kuo et al., 2004, JBC)。同时我们发现将survivin基因阻断,会促进抗癌药物抑制癌细胞的生长及促细胞凋亡之作用(Chao and Liu, 2006, Mol. Pharmacol.)。以COX-2的抑制剂,celecoxib及etodolac,发现抑制COX-2的活性会降低survivin蛋白表达,并加 强抗癌药物oxaliplatin的抗癌效果(Lin et al., 2005, Biochem. Pharmacol.)。Celecoxib会经由活化p38 MAP kinase路径,抑制大肠癌细胞中survivin蛋白的表达(Hsiao et al., 2007, TAAP)。而黄芩素(baicalein)会抑制膀胱癌细胞中survivin的表达,并诱发癌细胞凋亡(Chao et al., 2007, Mol. Cancer Ther.)。在抗癌奈米科技(Anticancer Nanotechnology)的研究,我们发现奈米钻石具有特殊萤光特性及作用,被选为生物物理期刊的封面(Chao et al., 2007, Biophys. J.)。此奈米材质不会造成正常细胞毒性及细胞凋亡,具有高度的生物相容性,并且奈米钻石在细胞内的萤光强度可被检测及量化 (Liu et al., 2007, Nanotechnology),我们进一步以蛇毒蛋白连结奈米钻石,可辨识细胞上的接受器(Liu et al., 2008, Nanotechnology),目前我们已经开发出奈米钻石携带抗癌药物的方法。此外,我们进一步开发奈米钻石作为癌细胞及干细胞的标定、侦测及追踪等 应用。

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

  • 免疫学:已检验出幽门螺旋杆菌对于细胞产生影响之主要分子—Hsp-60,正深入探讨其诱发免疫反应之主要机制,并研究Hsp60对于其他细胞所产生之影响
  • 微脂体 (Liposome):已完成此构型之建构,深入研究其快速且稳定吸附的作用力之机制及原理,同时利用此微脂体之特性包复药物,并结合导向分子
    以达到专一性输送药物之目的。
  • 抗体之制作及蛋白质工程:完成以VEGF及IgG Fc部份结合之抗体生产,纯化及应用。
    发现其可有效达到治疗肿瘤之目的。

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细胞骨架及型态发生实验室     黄兆棋博士 (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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