斑马鱼模型在药物筛选中的应用

斑马鱼具有子代数量多、体外受精、胚胎透明、可以做大规模遗传突变筛选等生物学特性, 因此成为一种良好的脊椎动物模式生物。随着研究的深入, 斑马鱼不仅应用于遗传学和发育生物学研究, 而且拓展和延伸到疾病模型和药物筛选领域。作为一种整体动物模型, 斑马鱼能够全面地检测评估化合物的活性和副作用, 实现高内涵筛选。近年来, 科学家们不断地发展出新的斑马鱼疾病模型和新的筛选技术, 并找到了一批活性化合物。这些化合物大多数在哺乳动物模型中也有相似的效果, 其中前列腺素E2(dmPGE2)和来氟米特(Leflunomide)已经进入临床实验, 分别用来促进脐带血细胞移植后的增殖和治疗黑素瘤。这些成果显示了斑马鱼模型很适合用于药物筛选。文章概括介绍了斑马鱼模型的特点和近年来在疾病模型和药物筛选方面的进展, 希望能够帮助人们了解斑马鱼在新药研发中的应用, 并开展基于斑马鱼模型的药物筛选。     

模式动物斑马鱼在神经系统疾病研究中的应用

近年来,斑马鱼作为一种新型模式动物被广泛地应用于发育学、遗传学、行为学和分子生物学等研究领域。其具有繁殖能力强、发育迅速且同步、体外受精和幼体透明等生物学和形态学特点,经广泛培养和筛选突变品种,目前斑马鱼品系资源丰富。与其他非脊椎模式动物相比,它与人类有更高的同源性。本文主要介绍斑马鱼作为一种理想的模式动物,结合其特殊的行为学检测手段和分子生物学特点,在研究神经系统疾病的发病机制、构建疾病模型和相应药物筛选等方面的应用。     

斑马鱼在生命科学研究中的应用

利用模式生物进行研究是推动生命科学发展的主要手段之一.斑马鱼已成为继小鼠之后的又一个重要的模式脊椎动物.本文将重点介绍斑马鱼在学习记忆和疾病研究领域中的应用,以及我国推动斑马鱼相关研究的策略.     

细胞自噬在斑马鱼中的研究进展

细胞自噬是一种维持细胞内稳态的重要方式,并被发现与许多人类疾病相关。由于其具有重大的理论研究价值和潜在应用前景,是近年来生命科学领域的热点之一。细胞自噬的功能与机制在物种间是高度保守的,对它的研究已在多种模式生物中展开。斑马鱼是一种常用的脊椎模式动物,具有影像学、遗传学和发育生物学等学科研究的优势,也可用于高通量药物筛选,是研究细胞自噬的理想材料。目前在斑马鱼中展开的细胞自噬相关研究取得了很多进展。本研究首先简要地描述了自噬的发生过程,重点综述应用于斑马鱼中的自噬检测方法,以及利用斑马鱼模型进行的与自噬相关人类疾病的研究。     

生物信息学及其在新药发现中的应用

人类基因组计划和蛋白质组计划的开展,为生物医药研究提供丰富的生物学信息。而在这纷繁复杂的生物信息中寻找合适的药物作用靶标是生物信息学的重要目的之一。目前,生物信息学已成为新药发现的重要工具和手段。     

斑马鱼在毒理学中的应用研究进展

药物毒性在很大程度上影响了新药的发现与应用,模式生物斑马鱼被越来越广泛地应用于药物毒理学研究.本文对斑马鱼模型在药物毒性研究(心脏毒性、肝毒性、肾毒性、神经毒性、遗传和跨代毒性以及致畸毒性)中的应用进展进行综述,并总结其相关优势及不足,为斑马鱼模型进一步应用于药物毒性的发现提供依据.     

斑马鱼研究走向生物医学

1972年美国俄勒冈大学George Streisinger教授开始研究斑马鱼(Danio rerio)至今, 斑马鱼以其独特的优点, 已经成为现代遗传学、发育生物学研究的重要模式动物。世界范围内斑马鱼研究群体的工作已奠定了较为完善的胚胎学、分子遗传学研究基础, 并且斑马鱼已被应用于开发人类重大疾病模型和药物筛选平台, 取得了许多有价值的研究成果。文章简述了斑马鱼成为模式动物的历史, 侧重介绍了业已建立的白血病、黑色素瘤、感染免疫疾病、神经疾病等斑马鱼模型, 以及利用斑马鱼进行小分子化合物/药物筛选和研发的现状。斑马鱼研究向生物医学方向的拓展, 必将为人类理解重大疾病发生机制、寻找疾病治疗方法, 为维护人类卫生、健康做出贡献。     

模型动物斑马鱼及其特定病原净化

虽然斑马鱼等实验用鱼已经成为生命科学研究的一类重要模型动物,但对于在集约化人工养殖过程中实验鱼的疾病却研究很少。实验用斑马鱼严重的健康问题使其在研究中常出现大面积甚至毁灭性的死亡。常见的感染也可以危及很多实验室的鱼群。因此,培育健康的实验用鱼群,建立必要的质量控制标准已经势在必行。本文收集和分析了大量相关的资料,为我国实验用鱼疾病的控制以及标准化研究和培育SPF斑马鱼提供帮助。     

斑马鱼与人类疾病模型的研究

斑马鱼是一种很好的用于研究脊椎动物胚胎学和发育遗传学的模型生物,它有其他模型生物所不具备的优点。最近研究较多的是在斑马鱼中建立人类疾病研究模型。本文就斑马鱼在造血障碍和心血管障碍等方面的疾病模型建立及主要的技术做简要论述。     

斑马鱼行为学实验在神经科学中的应用

斑马鱼作为新型模式动物的优势正在逐渐被人们所认识,其应用的领域也越来越宽广．斑马鱼在神经生物学中的应用,除了在发育方面比其他模式动物更具优势外,在行为学方面的应用也更加丰富．由于斑马鱼幼体在受精后前两天通体透明,眼睛大小占到大脑体积的二分之一以上,成鱼昼夜节律明显,对光反应强烈,因此斑马鱼在视觉领域应用的优势十分明显．斑马鱼的嗅觉、听觉器官都在体表可见,可以很容易地用行为学实验手段对嗅觉和听觉功能进行检测．斑马鱼习性好动,利用斑马鱼进行运动方面的行为学观察也非常便利．斑马鱼具有群聚习性,在社会生物学研究方面正得到越来越多的关注．斑马鱼行为学是一种比较简单而又有效地分析神经整合功能的方法,并形成了许多相关的实验模型．     

量子点在新药开发中的应用

由于具有优异的光学特性,量子点在生物医学领域内的研究和应用取得了一些有意义的进展,同时也引起了新药开发人员的兴趣.本文概述了量子点在新药开发中所具有的优势,分析了量子点在药物传输、药物筛选和药靶确证方面的潜在应用,进一步讨论了当前量子点应用于新药开发存在的问题和不足.     

"Click"化学在药物发现中的应用

“click”化学是最近几年发展起来的一种新技术,它在药物发现的许多方面均有着广泛的应用:快速合成小分子化合物库并从中筛选先导化合物、进行靶标导向的活性小分子合成以及在生物耦联技术等方面的应用。     

The integration of investigative toxicology in the drug discovery process

Summary— Integrating toxicology early in the drug discovery process adds value by providing the earliest possible identification of a compound's potential for toxicological and pathological effects relevant to intended clinical use. With this approach true ‘lead’ candidates, with a high probability of clinical success, are identified and advanced while reducing effort and resources expended on compounds without the requisite therapeutic index. Resources are focussed on the speed of getting a discovery ‘lead’ into early clinical development, defining the mechanisms of observed preclinical toxicity and their relevance to human use, and developing early safety data with in vitro test systems ahead of in vivo systems where possible, thus reducing animal use.     

Microarray technology GEM microarrays and drug discovery

Incyte Genomics' GEM™ Gene Expression Microarray is a proven genomics tool used by a large number of pharmaceutical companies to speed up the drug discovery and development process. The development and integration of this technology, together with Incyte's sequence databases and clone resources, have resulted in GEM microarrays that span approximately 60,000 human genes as well as approximately 60,000 plant, rat, mouse, yeast, and bacterial genes. The technology underlying the use of these arrays and their application to the drug discovery process is highlighted. Journal of Industrial Microbiology & Biotechnology (2002) 28, 180–185 DOI: 10.1038/sj/jim/7000136 Received 16 November 2000/ Accepted in revised form 01 March 2001     

A solid-phase glycosyltransferase assay for high-throughput screening in drug discovery research

Glycosyltransferases mediate changes in glycosylation patterns which, in turn, may affect the function of glycoproteins and/or glycolipids and, further downstream, processes of development, differentiation, transformation and cell-cell recognition. Such enzymes, therefore, represent valid targets for drug discovery. We have developed a solid-phase glycosyltransferase assay for use in a robotic high-throughput format. Carbohydrate acceptors coupled covalently to polyacrylamide are coated onto 96-well plastic plates. The glycosyltransferase reaction is performed with recombinant enzymes and radiolabeled sugar-nucleotide donor at 37°C, followed by washing, addition of scintillation counting fluid, and measurement of radioactivity using a 96-well -counter. Glycopolymer construction and coating of the plastic plates, enzyme and substrate concentrations, and linearity with time were optimized using recombinant Core 2 1-6-N-acetylglucosaminyltransferase (Core 2 GlcNAc-T). This enzyme catalyzes a rate-limiting reaction for expression of polylactosamine and the selectin ligand sialyl-Lewis^x in -glycans. A glycopolymer acceptor for 1-6-N-acetylglucosaminyltransferase V was also designed and shown to be effective in the solid-phase assay. In a high-throughput screen of a microbial extract library, the coefficient of variance for positive controls was 9.4%, and high concordance for hit validation was observed between the Core 2 GlcNAc-T solid-phase assay and a standard solution-phase assay. The solid-phase assay format, which can be adapted for a variety of glycosyltransferase enzymes, allowed a 5–6 fold increase in throughput compared to the corresponding solution-phase assay.     

Chemical Genetics: Drug Screens in Zebrafish

High throughput chemical genetic screens for compounds with specific biological activity in a whole organism are feasible using zebrafish embryos. At least two medium to large scale drug screens have been carried out to date, leading to the identification of compounds that disturb zebrafish development. Chemical genetics using zebrafish embryos may become an important step in the discovery of drugs and their targets.     

Genetics-directed drug discovery for combating Mycobacterium tuberculosis infection

Mycobacterium tuberculosis (Mtb), the pathogen of tuberculosis (TB), is one of the most infectious bacteria in the world. The traditional strategy to combat TB involves targeting the pathogen directly; however, the rapid evolution of drug resistance lessens the efficiency of this anti-TB method. Therefore, in recent years, some researchers have turned to an alternative anti-TB strategy, which hinders Mtb infection through targeting host genes. In this work, using a theoretical genetic analysis, we identified 170 Mtb infection-associated genes from human genetic variations related to Mtb infection. Then, the agents targeting these genes were identified to have high potential as anti-TB drugs. In particular, the agents that can target multiple Mtb infection-associated genes are more druggable than the single-target counterparts. These potential anti-TB agents were further screened by gene expression data derived from connectivity map. As a result, some agents were revealed to have high interest for experimental evaluation. This study not only has important implications for anti-TB drug discovery, but also provides inspirations for streamlining the pipeline of modern drug discovery.     

中国新药研究开发现状

随着国民经济的持续发展和生活水平的不断提高,健康状况与生命质量已经成为我国新时期社会发展的重大课题。人口老龄化和农村医药市场的拓展为生物医药产业提供了前所未有的成长空间。经过多年的不懈努力,我国自主的创新药物研究体系已经初步形成,以提升国际竞争力为导向,医药产业正在实现由仿制为主向创新为主的历史性转变。     

Novel computational biology methods and their applications to drug discovery

Computational biology methods are now firmly entrenched in the drug discovery process. These methods focus on modeling and simulations of biological systems to complement and direct conventional experimental approaches. Two important branches of computational biology include protein homology modeling and the computational biophysics method of molecular dynamics. Protein modeling methods attempt to accurately predict three-dimensional (3D) structures of uncrystallized proteins for subsequent structure-based drug design applications. Molecular dynamics methods aim to elucidate the molecular motions of the static representations of crystallized protein structures. In this review we highlight recent novel methodologies in the field of homology modeling and molecular dynamics. Selected drug discovery applications using these methods conclude the review.     

Endophytes: exploiting biodiversity for the improvement of natural product-based drug discovery

Abstract

Endophytes, microorganisms that colonize internal tissues of all plant species, create a huge biodiversity with yet unknown novel natural products, presumed to push forward the frontiers of drug discovery. Next to the clinically acknowledged antineoplastic agent, paclitaxel, endophyte research has yielded potential drug lead compounds with antibacterial, antiviral, antioxidant, insulin mimetic, anti-neurodegenerative and immunosuppressant properties. Furthermore, while being implicated in livestock neurotoxicosis, some endophyte-produced alkaloids have been shown to display insecticidal activity. The endophyte-host relationship is postulated to be a ‘balanced antagonism’. Moreover, the plausibility of horizontal gene transfer (HGT) hypothesis is taken into account. Knowledge of the genetic background of endophytic natural product biosynthesis is discussed on the basis of loline alkaloids, ergopeptines, lolitrems and maytansinoids. The current dynamic progress in genomics will contribute to a better understanding of endophytic microbes and to further exploiting them as a source of pharmaceutically relevant compounds.