Using a Sequence-to-Structure-to-Function Approach to Functionally Characterize Protein Coding Missense Mutations in the Human and Rat Genomes

使用序列到结构到功能的方法对人类和大鼠基因组中蛋白质编码错义突变进行功能表征

• 批准号: 9123595
• 负责人: Jeremy William Prokop
• 金额: $ 9.82万
• 依托单位: HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-29 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123595
• 关键词: Actins; Affinity; Age; Area; Award; Big Data; Big Data to Knowledge; Binding; Biochemical; Biological Assay; Biological Sciences; CLIA certified; Candidate Disease Gene; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Case Study; Cellular Morphology; Code; Computer Simulation; Computers; DNA; Data; Databases; Decision Trees; Development; Diagnostic; Dimerization; Disease; Disease model; Doctor of Philosophy; End stage renal failure; Evaluation; Filtration; Frequencies; Genes; Genetic; Genome; Genomics; Goals; Grant; Health; High-Throughput Nucleotide Sequencing; Human; Human Genetics; Human Genome; Informatics; Internet; Kidney; Knowledge; Lisinopril; Macromolecular Complexes; Malignant Neoplasms; Mentors; Methods; Missense Mutation; Molecular; National Heart, Lung, and Blood Institute; Online Systems; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Post-Translational Protein Processing; Postdoctoral Fellow; Precipitation; Process; Proteins; Proteomics; Protocols documentation; Quality Control; RNA; Rare Diseases; Rat Strains; Rattus; Reporting; Research; Research Personnel; SFN gene; Science of genetics; Scientist; Serine; Source; Structural Genes; Structure; Techniques; Testing; Training; Training Support; Translating; Validation; Variant; Wisconsin; clinical sequencing; cohort; computer science; data to knowledge; disease diagnosis; exome; exome sequencing; functional outcomes; genetic variant; genome database; genome sequencing; human disease; improved; interest; medical schools; mutant; novel; operation; programs; protein function; protein structure; rat genome; research study; response; screening; skills; statistics; tool; tool development; whole genome

DESCRIPTION: The goal of this BD2K K01 application is to provide Dr. Jeremy W. Prokop with the mentoring and training to be an independent investigator in big data to knowledge. Mentoring and training will be provided to Dr. Prokop in genomics, proteomics, computer science, and statistics to advance his skill to allow for independence. This will allow for further develop of his sequence-to-structure-to-function analysis for interpretation of protein coding genetic variants into a usable workflow available to other scientists. The mentoring throughout this award will be from Dr. Howard Jacob, a leader in rat/human genetics and tool development to understand variants in whole genomes. Additionally, Dr. Andrew Greene serves as a co-mentor to help advance skills in proteomics and Dr. Christina Kendziorski as a co-mentor to advance statistical tools/approaches. The Medical College of Wisconsin (MCW) is a leader in the use of whole genome sequencing in understanding human health, with a Cap/CLIA certified clinical sequencing facility, tools for identifying genetic variants from whole genomes (such as Carpe Novo), and operation of databases like the Rat Genome Database. These tools and knowledge at MCW will serve as an asset for the training and completion of the Aims in this award. Dr. Prokop's research focus in this grant is to further expand the sequence-to-structure-to-function approaches he developed during his Ph.D. and initial postdoc into a workflow and web submission server for other users. Aim 1 of the grant organizes these steps into a workflow allowing for the development of the web based submission server. To test the workflow, 75 candidate genes for cardiovascular disease will be screened. Initial use of the approach has revealed hypotheses for how genetic variants in Havcr1 and Shroom3 result in altered cardiovascular drug response or disease. Variants in these two proteins will be biochemically characterized using a novel decision tree to standardize experiments (Aim 2) and to serve as a quality control for the approaches of Aim 1. From the results of the 75 screened cardiovascular genes, the four genes with the highest confidence score will be validated using the biochemical decision tree in year four and five of this award serving as an additional quality control for the approaches in Aim 1. This grant will provide the training and support for Dr. Prokop to be integrated into the Medical College of Wisconsin's Clinical Sequencing program, allowing for additional R01 proposals for validation of genetic causes of disease, and facilitate the development of Dr. Prokop into an independent researcher in the use of big data.

描述：该BD2K K01应用程序的目的是为Jeremy W. Prokop博士提供指导和培训，成为大数据知识的独立研究者。将向Prokop博士提供基因组学，蛋白质组学，计算机科学和统计数据的指导和培训，以提高其允许独立性的技巧。这将允许进一​​步 开发他的序列到结构到功能分析，以将蛋白质编码的遗传变异解释为其他科学家可用的工作流程。整个奖项的指导将来自霍华德·雅各布（Howard Jacob）博士，他是老鼠/人类遗传学和工具开发的领导者，以了解整个基因组中的变体。此外，安德鲁·格林（Andrew Greene）博士还担任促进蛋白质组学技能的同事，而克里斯蒂娜·肯德斯基（Christina Kendziorski）博士则是推进统计工具/方法的同事。威斯康星州医学院（MCW）是使用CAP/CLIA认证的临床测序设施，用于了解整个基因组测序的领导者，用于鉴定来自整个基因组（例如Carpe Novo）的遗传变异的工具，以及诸如Rat Rat Genome数据库之类的数据库的操作。 MCW的这些工具和知识将成为该奖项中培训和完成目标的资产。 Prokop博士在这笔赠款中的研究重点是进一步扩展他在博士学位期间开发的序列到结构的方法。最初的DOSTOC进入了其他用户的工作流和Web提交服务器。 AIM 1的赠款将这些步骤组织到工作流程中，以允许开发基于Web的提交服务器。为了测试工作流程，将筛选75个用于心血管疾病的候选基因。该方法的最初使用揭示了HAVCR1和Shroom3中遗传变异的假设如何导致心血管药物反应或疾病改变。这两种蛋白质中的变体将在生物化学上使用新颖的决策树进行生化特征，以标准化实验（AIM 2），并作为目标1的方法的质量控制。从75个筛选的心血管基因的结果来看，具有最高置信度得分的四个基因将在该奖励中验证该奖励的四个培训，以验证该奖励的培训，以验证该奖励的五年级，以进一步的质量质量，作为质量质量的质量，作为质量的质量，并将其作为一个质量的培训。让Prokop博士纳入威斯康星州医学院的临床测序计划，允许其他R01提案以验证疾病的遗传原因，并促进Prokop博士的发展成为一名独立研究人员，以使用大数据。