Statistical & Computational Method For Molecular Biology

统计

• 批准号: 7145131
• 负责人: peter j munson
• 金额: --
• 依托单位: CENTER FOR INFORMATION TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7145131
• 关键词: classification; computational biology; method development; molecular biology; protein structure; statistics /biometry; structural biology

Mathematical and statistical modeling techniques are relevant to biomedical investigations at a variety of scales and in a variety of contexts. Our Lab applies expertise in the mathematical, statistical and computing sciences to address novel problems arising in cutting edge areas of biomedical research. In a joint study with investigators in Laboratory of Molecular Biology, NCI and Institut National de la Recherche Agronomique (INRA), France, we are attacking the problem of protein structure classification, with the goal of improving automated methods for recognition and classification of protein domains in three dimensional structures. Domains are thought to be the building blocks of complex structures, and often determine protein function. Our current project compares two existing protein structure similarity detection methods (VAST and SHEBA) and contrasts them with a manually curated protein classification, SCOP. A large representative database of structures has been used to identify ambiguous classes of proteins which neither automated method effectively distinguishes. Automated hierarchical clustering based on VAST and SHEBA similarity scores has been tested and compared to the SCOP classification. A manuscript describing our results is under review. With an investigator in the Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, and with another investigator from Imperial College, London, who was a visitor to NCI, we have studying the physical topology of gene and chromosome placement in cell nuclei. This work requires careful statistical analysis on data collected of gene and chromosome placement data. We have shown that in mice, the gene MASH1, involved in early embryonic neurogenesis, is preferentially placed in the nuclear periphery in embryonic stem cells, but migrates towards the nuclear center after commitment to neural development. It was shown, too, that the physical change in location was coupled to changes in expression level and to changes in chromatin structure along a 2MB region of the genome centered about the MASH1 locus. A manuscript describing this is under referee review. With an investigator in the Division of International Epidemiology, Fogarty International Center, we have developed a phenomenological model of Plasmodium parasite/red blood cell dynamics, and have used it to examine the consequences of strategies of attack of the different Plasmodium species that attack humans. Currently, we are investigating consequences of dual P. vivax- P. falciparum infection. (PCR studies indicate that about 10% of all human malaria cases are dual P. vivax-P. falciparum infections.) Our studies indicate transients in red blood cell production induced in response to P. falciparum invasion of such cells can greatly boost the parasitemia of P. vivax, even inducing a cryptic infection into a more dangerous phase. A manuscript describing this work is under review. Investigators in NICHD and CIT have created Extended Microcapture Dissection (or XMD), a major revision of the laser capture microdissection (LCM) device that was developed here at NIH in the mid 1990?s. In this new form of microtransfer using thermoplastic films, the intrinsic absorption of stained tissue heats up the polymer and causes it to melt and form a thermoplastic bond similar to that in LCM. We have performed thermal diffusion modeling to assist in optimizing the design or operations of this new device. Prototypes have been built and the focus is currently on the testing of prototypes. In a continuing project with investigators in the Laboratory of Integrative and Medical Biophysics, NICHD related to the development of diffusion tensor MRI on using Non-Uniform Rational B-Splines (NURBS) for extracting geometrical features of the basic brain anatomy, with ultimate goal of developing a continuous tensor model based on NURBS, we showed how some important differential geometric quantities can be determined more reliably than with other models. This is published in a book chapter. In another project with the same group we propose a novel method for performing true spectral decomposition of the tensor valued random variables, rather than performing it using rasterized (vectorized) tensors. In a project, with investigators of NIMH, we analyzed multiple-electrode recordings from in-vitro neural network preparations in order to deduce the underlying cortical networks topology. We obtained the results for the organotypic rat brain preparations, which show a strong "small world" property, meaning high clustering among the nodes and short node-to-node distances. We conducted large scale simulations to verify those results. The ultimate goal is to understand the relationship between the topology of the network and the functions that it performs.

数学和统计建模技术与各种规模和各种背景下的生物医学调查有关。我们的实验室应用数学、统计和计算科学方面的专业知识来解决生物医学研究前沿领域中出现的新问题。 在与NCI分子生物学实验室和法国国家农学研究所(INRA)的研究人员联合进行的一项研究中，我们正在解决蛋白质结构分类的问题，目的是改进三维结构中蛋白质结构域的自动识别和分类方法。结构域被认为是复杂结构的基石，通常决定蛋白质的功能。我们目前的项目比较了两种现有的蛋白质结构相似性检测方法(Vavast和Sheba)，并将它们与手动精选的蛋白质分类SCOP进行了对比。一个具有代表性的大型结构数据库已经被用来识别模糊的蛋白质类别，而这些模糊类别的蛋白质都不是自动方法有效区分的。基于Vavast和Sheba相似性分数的自动层次聚类已经过测试，并与SCOP分类进行了比较。一份描述我们结果的手稿正在审查中。 与国家癌症研究所受体生物学和基因表达实验室的一名研究人员，以及另一名访问NCI的伦敦帝国理工学院的研究人员，我们研究了基因的物理拓扑和染色体在细胞核中的放置。这项工作需要对收集的基因和染色体放置数据进行仔细的统计分析。我们已经证明，在小鼠中，参与早期胚胎神经发生的基因MASH1在胚胎干细胞中优先放置在核外围，但在致力于神经发育后向核中心迁移。研究还表明，位置的物理变化与表达水平的变化以及以MASH1基因为中心的基因组2MB区域染色质结构的变化有关。一份描述这一点的手稿正在接受裁判的审查。 与Fogarty国际中心国际流行病学部的一名研究人员一起，我们开发了一个疟原虫/红细胞动力学的现象学模型，并用它来检验攻击人类的不同疟原虫物种攻击策略的后果。目前，我们正在调查间日疟原虫和恶性疟原虫双重感染的后果。(聚合酶链式反应研究表明，约10%的人类疟疾病例是间日疟原虫和间日疟原虫双重感染。恶性疟原虫感染)我们的研究表明，对恶性疟原虫入侵的红细胞产生的瞬时反应可以极大地促进间日疟原虫的原虫血症，甚至诱导隐蔽感染进入更危险的阶段。描述这项工作的手稿正在审查中。 NICHD和CIT的研究人员发明了扩展微捕获解剖(或XMD)，这是上世纪90年代中期在美国国立卫生研究院开发的激光捕获显微解剖(LCM)设备的主要修订版？S。在这种使用热塑性薄膜进行微转移的新形式中，染色组织的本征吸收会加热聚合物，使其熔化并形成类似于LCM的热塑性键。我们已经进行了热扩散建模，以帮助优化这一新设备的设计或操作。原型已经建立，目前的重点是原型的测试。 在NICHD与医学生物物理实验室的研究人员继续进行的项目中，NICHD与扩散张量MRI的发展有关，使用非均匀有理B-样条(NURBS)来提取基本大脑解剖的几何特征，最终目标是开发基于NURBS的连续张量模型，我们展示了如何比其他模型更可靠地确定一些重要的微分几何量。这是在一本书的章节中发表的。在同一组的另一个项目中，我们提出了一种新的方法来执行张量值随机变量的真谱分解，而不是使用光栅化(矢量化)张量来执行它。 在一个项目中，我们与NIMH的研究人员一起，分析了来自体外神经网络准备的多电极记录，以推断潜在的皮质网络拓扑。我们得到了器官型大鼠脑制剂的结果，它显示出强烈的小世界属性，即节点之间的高度聚集和节点到节点的短距离。我们进行了大规模的模拟来验证这些结果。最终目标是了解网络拓扑与其执行的功能之间的关系。