Biomedical Imaging

该项目使用成像科学技术来分析许多类型的生物，临床和生物医学图像。目前的研究集中在两个一般领域：（1）使用电子显微镜和NMR光谱的图像处理的大分子结构生物学和（2）先进的生物医学和实验室成像软件的开发。 (1)成像科学实验室与各研究所开展了一项重大的合作研究工作，涉及在结构生物学中使用图像处理技术和先进的计算技术，以分析电子显微照片和核磁共振光谱，目的是确定大分子结构。近年来的研究主要集中在二十面体病毒衣壳的三维重建、分析和解释上。正在进行的研究涉及与疱疹病毒和乳头瘤病毒以及其他二十面体病毒衣壳相关的结构分析。 乳头瘤病毒（例如HPV-16）编码两种衣壳蛋白，L1和L2。主要衣壳蛋白L1可以自发地组装成72-五聚体二十面体结构，其非常类似于天然病毒体。虽然次要衣壳蛋白L2不是衣壳形成所必需的，但它被认为参与病毒基因组的衣壳化，并在病毒感染性进入途径中发挥许多重要作用。L2的丰度及其在病毒粒子内的排列仍不清楚。冷冻电子显微镜和差异的3D重建分析纯化的衣壳揭示了二十面体有序的L2特定密度下的轴向管腔的每个L1壳粒。L2特定密度的二十面体有序细丝也延伸到L1衣壳壳的底板下，提高了组装的病毒粒子内同型L2相互作用的可能性。我们已经使用延时冷冻电子显微镜和图像分析来研究在293 T细胞中组装的HPV-16衣壳的成熟。主要的衣壳蛋白，L1，最初形成一个松散连接的原衣壳，在体外条件下，经过几个小时浓缩成更熟悉的60 nm直径的乳头状瘤病毒衣壳。在这个过程中，原衣壳直径缩小约5%;其五聚体衣壳结构发生变化，最明显的是在其轴向区域;相邻衣壳之间的相互作用表面被巩固。这些结构变化伴随着二硫键交联的形成，其增强成熟衣壳的稳定性。不交联的C175 S突变体显示出类似的成熟相关的结构变化，但衣壳在其他类似条件下显著更大。我们的结论是，所观察到的结构尺寸的变化有利于成熟，但交联形成所需的锁定衣壳进入成熟状态。 我们还一直在开发计算工具，用于使用核磁共振数据研究生物大分子的结构和动力学。我们积极支持使用Xplor-NIH生物分子结构测定软件包的校内和校外社区。Xplor-NIH的开发工作在以下领域继续进行：（a）在使用Python和TCL脚本接口方面取得进一步进展，并增加了大量文档;（B） 通过结合NMR和溶液X射线散射技术的信息，已经获得了溶液中DNA动力学性质的第一幅真实的图片;（c）现在可以直接根据溶液X射线散射和小角中子散射数据来改进分子结构。 (2)成像科学实验室致力于为NIH的各种临床和生物医学活动提供计算和工程专业知识。具体而言，PET、超声、CT、MRI、EPR、显微镜、癌症研究中的成像以及与神经功能障碍相关的成像已经以多种方式得到支持。为了支持NIH内部计划的科学研究，CIT开发并继续增强一个复杂的独立于平台的，n维的，可扩展的图像处理和可视化应用程序。MIPAV（医学图像处理分析和可视化）是一种应用程序，可以对生物医学成像模式（从微观到宏观）进行定量分析和可视化，并被NIH和世界各地的研究人员使用。在NIH，MIPAV已被用于分析CT数据集中的解剖结构，辅助射频消融（RFA）手术相关图像数据集的预处理分析（配准和分割），NIMH的MRI数据集分析，并已被NCI用于分析2D和3D显微镜样本。我们还将继续支持NEI对眼部疾病的研究，并支持对骨关节炎倡议（Osteoarthritis Initiative）的图像数据进行分析，这是一项由美国国立卫生研究院（National Institutes of Health）赞助的全国性研究，将有助于我们更好地了解如何预防和治疗膝关节骨关节炎。此外，我们管理和开发国家自闭症研究数据库（NDAR）项目的主要组成部分，该项目是由美国国立卫生研究院创建的合作生物医学信息系统，旨在提供国家资源以支持和加速自闭症研究。NDAR是一个支持自闭症研究活动的信息系统集合，包括基因组，成像，实验室，临床和行为数据源。它将为数据仓、数据输入系统和共同措施及其文件的集中来源提供核心技术。它将支持大规模、多地点项目以及试点研究和基础科学调查。

This project uses imaging science techniques to analyze many types of biological, clinical and biomedical images. Current research focuses on two general areas: (1) the structural biology of macromolecules using image processing of electron micrographs and NMR spectroscopy and (2) the development of sophisticated biomedical and laboratory imaging software. (1) The Imaging Sciences Laboratory has a major collaborative research effort with the Institutes involving the use of image processing techniques and advanced computational techniques in structural biology to analyze electron micrographs and NMR spectra with the goal of determining macromolecular structures. Recent efforts have concentrated on the 3D reconstruction, analysis and interpretation of the structures of icosahedral virus capsids. Ongoing research involves analyses of structures related to herpesvirus and papillomairus as well as other icosahedral virus capsids. Papillomaviruses (e.g. HPV-16) encode two capsid proteins, L1 and L2. The major capsid protein, L1, can assemble spontaneously into a 72-pentamer icosahedral structure that closely resembles native virions. Although the minor capsid protein L2 is not required for capsid formation, it is thought to participate in encapsidation of the viral genome, and plays a number of essential roles in the viral infectious entry pathway. The abundance of L2 and its arrangement within the virion remain unclear. Cryo-electron microscopy and difference 3D reconstruction analysis of purified capsids revealed an icosahedrally-ordered L2-specific density beneath the axial lumen of each L1 capsomer. Icosahedrally-ordered filaments of L2-specific density also extended under the floor of the L1 capsid shell, raising the possibility of homotypic L2 interactions within assembled virions. We have used time-lapse cryo-electron microscopy and image analysis to study the maturation of HPV-16 capsids assembled in 293T cells. The major capsid protein, L1, initially forms a loosely connected procapsid which, under in vitro conditions, condenses over several hours into the more familiar 60 nm-diameter papillomavirus capsid. In this process, the procapsid shrinks by ~ 5% in diameter; its pentameric capsomers change in structure, most markedly in their axial region; and the interaction surfaces between adjacent capsomers are consolidated. These structural changes are accompanied by the formation of disulfide crosslinks that enhance the stability of the mature capsid. The C175S mutant, which does not crosslink, shows similar maturation-related structural changes but capsids are significantly larger, under otherwise similar conditions. We conclude that the observed structural size changes facilitates maturation, but crosslink formation is required to lock the capsid into the mature state. We have also been developing computational tools for the study of the structure and dynamics of biological macromolecules using NMR data. We are actively supporting the intra- and extramural communities which use the Xplor-NIH biomolecular structure determination software package. Development of Xplor-NIH has continued in the following areas: (a) further progress in the use of the Python and TCL scripting interfaces and the addition of extensive documentation; (b) the first realistic picture of the dynamical nature of DNA in solution has been obtained by combining information from NMR and Solution X-ray scattering techniques; (c) it is now possible to refine molecular structures directly against solution X-ray scattering and small-angle neutron scattering data. (2) The Imaging Sciences Laboratory has a commitment to providing computational and engineering expertise to a variety of clinical and biomedical activities at NIH. Specifically, PET, ultrasound, CT, MRI, EPR, microscopy, imaging in cancer research, and imaging related to neural dysfunction have been supported in a number of ways. To support scientific in the NIH intramural program, CIT has developed and continues to enhance a sophisticated platform-independent, n-dimensional, extensible image processing and visualization application. The MIPAV (Medical Image Processing Analysis and Visualization) is an application that enables quantitative analysis and visualization of biomedical imaging modalities (from micro to macro) and is used by researchers at NIH and around the world. At NIH, MIPAV has been used to analyze anatomical structures in CT datasets, assist in pretreatment analysis (registration and segmentation) of image datasets associated with radio frequency ablation (RFA) procedures, analysis of MRI datasets for NIMH, and has been used by NCI for the analysis of 2D and 3D microscopic samples. We also continue to support the NEI with research of diseases of the eye and support analysis of image data from the Osteoarthritis Initiative, a nationwide research study sponsored by the National Institutes of Health, that will help us better understand how to prevent and treat knee osteoarthritis. In addition, we manage and develop major components of the National Database for Autism Research (NDAR) project which is a collaborative biomedical informatics system created by the National Institutes of Health to provide a national resource to support and accelerate research in autism. NDAR is a collection of information systems supporting the full range of autism research activities, including genomic, imaging, laboratory, clinical, and behavioral data sources. It will provide the core technology for a data warehouse, a data-entry system, and a centralized source for common measures and their documentation. It will support large-scale, multi-site projects as well as pilot studies and basic science investigations.