Computational Methods for Functional Genomic Discovery from Gene Knockout Studies

基因敲除研究中功能基因组发现的计算方法

• 批准号: 7999392
• 负责人: Kenneth L Drake
• 金额: $ 53.8万
• 依托单位: SERALOGIX
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-04 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999392
• 关键词: Adopted; Algorithms; Area; Biological; Biology of Aging; Biomedical Research; Cell Cycle; Collection; Communities; Complex; Computational Technique; Computing Methodologies; Congenital Abnormality; Coupled; Data; Databases; Development; Developmental Biology; Diagnostic; Disease; Embryo; Evaluation; Future; Gene Expression; Gene Proteins; Generations; Genes; Genetic; Genomics; Genotype; Goals; Health; Hereditary Disease; Imagery; In Vitro; Information Resources; Institutes; Intervention; Investigation; Knock-out; Knockout Mice; Knowledge; Knowledge Extraction; Learning; Literature; Medical; Medicine; Methods; Modeling; Molecular; Molecular Target; Mus; Names; Neural tube; Pathogenesis; Pattern; Pattern Recognition; Performance; Phase; Phenotype; Planning Techniques; Process; Proteomics; Provider; Public Health; Publishing; Recurrence; Regulation; Regulator Genes; Research; Research Personnel; Resources; Sampling; Scheme; Scientist; Signal Transduction; Software Tools; Statistical Methods; Structure; System; Systems Biology; Techniques; Testing; Texas; Time; Validation; base; biological research; biological systems; comparative; computer based statistical methods; computerized tools; data modeling; drug development; embryonic stem cell; functional genomics; gene discovery; improved; innovation; insight; knockout gene; malformation; man; mathematical model; method development; mouse genome; network models; novel; null mutation; protein expression; public health relevance; research study; response; scale up; simulation; software development; stem; tool

DESCRIPTION (provided by applicant): The overall Phase II objective is to continue the development/validation of new system biology computational tools for inferencing gene regulatory relationships from gene expression data obtained from multi-perturbation gene knockout experiments. NIH's Knockout Mouse Project (KOMP) is an initiative to generate a public resource of mouse embryonic stem (ES) cells containing a null mutation in every gene in the mouse genome - important for deciphering the complexity of biological systems of mice and ultimately man. It is anticipated that a new generation of multi-perturbation/KO studies with a biological system perspective will emerge in all areas of biomedical research. New computational tools for deciphering genetically regulated responses (genotype-to- phenotype signaling cascades) will significantly aid in advancing our understanding of the molecular targets and mechanisms of many diseases. Today, researchers need new tools to deal with and decipher the tremendous volumes of gene/protein expression data generated from multi-perturbation investigations. Seralogix's Phase II efforts focus on improving and creating new functionality for learning larger scale (biological system level) gene regulatory networks and integrating this network learning functionality into our existing Biosystem Analysis Framework (BAF). Our BAF is comprised of a suite of integrated mathematical analysis and modeling tools and databases. The BAF core tools are based on Dynamic Bayesian Networks (DBNs). DBNs allow us to systematically integrate prior knowledge with empirical time-course expression data for modeling, pattern recognition and eventually biological system genetic network learning as proposed herein. Our algorithmic innovation, proven feasible in Phase I, is the incorporation of biological prior knowledge and multi-perturbation data with our DBNs for enabling a genetic network learning approach. This approach is based on well established Bayesian statistical methods that we adopt in a sampling scheme enhanced with biological prior knowledge to overcome the intrinsic difficulty of structure learning from sparse and noisy gene expression data. We show in Phase I that prior-knowledge, coupled with Bayesian network learning methods and multi-perturbation/KO experimental data, resulted in reliable gene regulatory relationship identification. We believe this approach can be scaled up, leading to a more robust mathematical/functional system level model. Further, we believe that integrating genetic network learning into Seralogix's BAF will provide an important new tool for identifying novel gene regulatory relations and insights into disease processes and have significant commercial potential for Seralogix. We will be collaborating with the Texas Institute of Genomic Medicine as a provider of mouse gene expression KO data who are studying the genomic causes of birth defects. Our Phase II aims include: 1) scaling our approach to support biological system level network learning; 2) statistical assessment and biological validation of our learned networks; 3) developing new tools/techniques to interrogate the resulting system network models so biologist can extract important knowledge. PUBLIC HEALTH RELEVANCE: It is one of the ultimate goals for modern biological research to fully elucidate the intricate interplays and the regulations of the molecular determinants that control health and disease, to name a few, cell cycling, developmental biology, aging, and the progressive and recurrent pathogenesis of complex diseases. Having new computational methods (software tools) for identifying and deciphering genetically regulated response (e.g. signaling cascades) will significantly aid in advancing our understanding of the molecular targets and mechanisms of many diseases of high public health concern. The discovery of underlying genetic function and relationships will be extremely important for making medical breakthroughs, especially for the safe and effective development of drugs and diagnostics. Today, researchers are hindered by the tremendous volumes of gene/protein expression data generated from knockout investigations. Computational tools that transform these volumes of raw genomic/proteomic data to actionable knowledge via mathematical modeling will help guide and accelerate researchers' investigations of genetic disorder and identifying targets of intervention and treatment.

描述（由申请人提供）：第二阶段的总体目标是继续开发/验证新的系统生物学计算工具，用于从多扰动基因敲除实验获得的基因表达数据推断基因调控关系。美国国立卫生研究院 (NIH) 的基因敲除小鼠项目 (KOMP) 是一项旨在生成小鼠胚胎干 (ES) 细胞公共资源的计划，其中小鼠基因组中的每个基因均含有无效突变，这对于破译小鼠乃至人类生物系统的复杂性非常重要。预计从生物系统角度进行的新一代多扰动/KO研究将出现在生物医学研究的所有领域。用于破译基因调控反应（基因型到表型信号级联）的新计算工具将极大地有助于增进我们对许多疾病的分子靶点和机制的理解。如今，研究人员需要新的工具来处理和破译多扰动研究产生的大量基因/蛋白质表达数据。 Seralogix 的第二阶段工作重点是改进和创建新功能，用于学习更大规模（生物系统级）基因调控网络，并将该网络学习功能集成到我们现有的生物系统分析框架 (BAF) 中。我们的 BAF 由一套集成的数学分析和建模工具以及数据库组成。 BAF 核心工具基于动态贝叶斯网络 (DBN)。 DBN 使我们能够系统地将先验知识与经验时间过程表达数据相结合，以进行建模、模式识别以及最终的生物系统遗传网络学习。我们的算法创新在第一阶段被证明是可行的，它将生物先验知识和多扰动数据与我们的 DBN 相结合，以实现遗传网络学习方法。这种方法基于完善的贝叶斯统计方法，我们在利用生物学先验知识增强的采样方案中采用该方法，以克服从稀疏和嘈杂的基因表达数据中进行结构学习的内在困难。我们在第一阶段表明，先验知识加上贝叶斯网络学习方法和多扰动/KO 实验数据，可以实现可靠的基因调控关系识别。我们相信这种方法可以扩大规模，从而形成更强大的数学/功能系统级模型。此外，我们相信，将遗传网络学习整合到 Seralogix 的 BAF 中将为识别新的基因调控关系和洞察疾病过程提供重要的新工具，并为 Seralogix 带来巨大的商业潜力。我们将与德克萨斯基因组医学研究所合作，作为小鼠基因表达 KO 数据的提供者，该研究所正在研究出生缺陷的基因组原因。我们第二阶段的目标包括：1）扩展我们的方法以支持生物系统级网络学习； 2）对我们学习的网络进行统计评估和生物学验证； 3）开发新的工具/技术来询问所产生的系统网络模型，以便生物学家能够提取重要的知识。 公共健康相关性：现代生物学研究的最终目标之一是充分阐明控制健康和疾病的分子决定因素之间错综复杂的相互作用和调控，例如细胞周期、发育生物学、衰老以及复杂疾病的进行性和复发性发病机制。拥有用于识别和破译基因调控反应（例如信号级联）的新计算方法（软件工具）将极大地有助于增进我们对许多公共卫生高度关注疾病的分子靶点和机制的理解。潜在遗传功能和关系的发现对于医学突破极其重要，特别是对于药物和诊断的安全有效的开发。如今，研究人员受到基因敲除研究产生的大量基因/蛋白质表达数据的阻碍。通过数学模型将大量原始基因组/蛋白质组数据转化为可操作知识的计算工具将有助于指导和加速研究人员对遗传性疾病的研究并确定干预和治疗的目标。