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

描述：此BD 2K K 01应用程序的目标是为Dr. Jeremy W. Prokop与指导和培训是一个独立的调查员在大数据的知识。将为Prokop博士提供基因组学、蛋白质组学、计算机科学和统计学方面的指导和培训，以提高他的技能，使他能够独立。这将允许进一步 他将自己的序列-结构-功能分析方法发展为其他科学家可用的工作流程，用于解释蛋白质编码遗传变异。整个奖项的指导将来自霍华德雅各布博士，在大鼠/人类遗传学和工具开发的领导者，以了解整个基因组的变异。此外，安德鲁格林博士担任共同导师，以帮助推进蛋白质组学的技能和克里斯蒂娜Kendziorski博士作为共同导师，以推进统计工具/方法。威斯康星州医学院（MCW）是使用全基因组测序来了解人类健康的领导者，拥有Cap/CLIA认证的临床测序设施，用于从全基因组中识别遗传变异的工具（如Carpe Novo），以及像大鼠基因组数据库这样的数据库的操作。MCW的这些工具和知识将作为培训和完成本奖项目标的资产。Prokop博士在这项资助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-结构-功能方法。和初始博士后到工作流和Web提交服务器为其他用户。该补助金的目标1将这些步骤组织成一个工作流程，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个心血管疾病的候选基因。该方法的初步使用揭示了Havcr 1和Shroom 3的遗传变异如何导致心血管药物反应或疾病改变的假设。这两种蛋白质的变体将使用新的决策树进行生物化学表征，以标准化实验（目标2）并作为目标1方法的质量控制。从75个筛选的心血管基因的结果中，具有最高置信度得分的四个基因将在该奖项的第四年和第五年使用生化决策树进行验证，作为目标1中方法的额外质量控制。这笔赠款将为Prokop博士提供培训和支持，使其融入威斯康星州医学院的临床测序计划，允许额外的R 01提案用于验证疾病的遗传原因，并促进Prokop博士发展成为使用大数据的独立研究人员。

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.