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尺度和各种情况下的生物医学研究有关。我们的实验室在数学，统计和计算科学方面运用专业知识来解决生物医学研究尖端领域中产生的新问题。 在与分子生物学实验室，NCI和法国国家DE LA Recherche Agronomique（INRA）的研究人员的联合研究中，我们正在攻击蛋白质结构分类的问题，目的是改善自动化方法的识别和分类蛋白质领域的分类在三维结构中。域被认为是复杂结构的基础，通常决定蛋白质功能。我们当前的项目比较了两种现有的蛋白质结构相似性检测方法（广泛和Sheba），并将它们与手动策划的蛋白质分类SCOP进行了对比。大型结构的代表性数据库已被用来识别模棱两可的蛋白质类别，这些蛋白质均未有效地区分自动化方法。基于广泛的SHEBA相似性得分的自动层次聚类已经进行了测试，并将其与SCOP分类进行了比较。描述我们结果的手稿正在审查中。 随着国家癌症研究所的受体生物学和基因表达实验室的研究人员，以及来自伦敦帝国学院的另一位研究者，他是NCI的访客，我们研究了基因和染色体在细胞核中的物理拓扑。这项工作需要对收集的基因和染色体放置数据的数据进行仔细的统计分析。我们已经表明，在小鼠中，与早期胚胎神经发生有关的基因Mash1优先放置在胚胎干细胞中的核周围，但在承诺神经发育后向核中心迁移。也表明，位置的物理变化与表达水平的变化以及沿着MASH1基因座的基因组的2MB区域的变化以及染色质结构的变化。描述此事的手稿在裁判审查下。 在Fogarty国际中心的国际流行病学划分的研究者中，我们开发了寄生虫/红细胞动力学的现象学模型，并使用它来研究攻击人类的不同疟原虫攻击策略的后果。目前，我们正在研究双疟原虫恶性疟原虫感染的后果。 （PCR的研究表明，所有人类疟疾病例中约有10％是双疟原虫。）我们的研究表明，响应于恶性疟原虫侵袭此类细胞而引起的红细胞产生中的瞬时，可以极大地增强寄生虫病。 Vivax的P.，甚至诱导隐性感染到更危险的阶段。描述这项工作的手稿正在审查中。 NICHD和CIT的研究人员创建了扩展的微型裁缝（或XMD），这是1990年中期在NIH开发的激光捕获微分辨率（LCM）设备的主要修订。在这种新形式的微转移使用热塑性膜中，染色组织的内在吸收加热聚合物并导致其融化并形成与LCM中类似的热塑性键。我们已经进行了热扩散建模，以帮助优化该新设备的设计或操作。已经建立了原型，目前的重点放在原型的测试上。 在与整合性和医学生物物理学实验室的研究人员进行的一个持续项目中，NICHD与使用不均匀的理性B-Splines（NURB）相关的扩散张量MRI的发展，以提取基本脑解剖学的几何特征，并具有最终的目标。开发基于NURB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差异几何量。这是在书籍章节中发表的。在另一个组的另一个项目中，我们提出了一种新的方法，用于对张量的有价值的随机变量进行真实的光谱分解，而不是使用栅格化（矢量化的）张量进行操作。 在一个项目中，与NIMH的研究者一起，我们分析了体外神经网络制剂的多电极记录，以推断基础的皮质网络拓扑。我们获得了器官型大鼠脑制剂的结果，这些结果显示出强大的“小世界”特性，这意味着节点之间的聚类高和短节点距离距离。我们进行了大规模模拟以验证这些结果。最终目标是了解网络拓扑与其执行功能之间的关系。