Illuminating Druggable Dark Matter

照亮可药物暗物质

• 批准号: 9454184
• 负责人: LILY Y JAN
• 金额: $ 239.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9454184
• 关键词: Alleles; Aloral; Antibodies; Area; Big Data; Biochemical; Bioinformatics; Biological Assay; Biological Process; Biology; Cell Line; Cell model; Cells; Classification; Communities; Complement; Complex; Computer Analysis; Data; Data Set; Development; Developmental Biology; Disease; Expression Library; Family member; Fostering; Gene Expression Profile; Genes; Genetic; Goals; Health; Hormones; Human; Human Cell Line; Human Genome; Immunology; Individual; Information Networks; Ion Channel; Ion Transport; Ions; Malignant Neoplasms; Measurement; Metabolic; Modeling; Molecular; Mus; Muscle Contraction; Mutate; Network-based; Neurobiology; Pattern; Phenotype; Physiology; Post-Translational Protein Processing; Protein Subunits; Proteins; Proteomics; Reagent; Research; Research Personnel; Resources; Role; Scheme; Signal Transduction; Specialist; Sum; System; Technology; Time; Tissues; United States National Institutes of Health; Validation; Work; authority; base; dark matter; disease-causing mutation; disorder subtype; field study; flexibility; gene function; human disease; in vivo; member; mouse model; neuronal excitability; neurotransmission; new technology; novel; programs; protein complex; protein expression; synergism; tool

Project Summary The goal of this project is to generate data and reagents that help uncover critical functions of the poorly characterized members of ion channels. We prioritize mouse models, given the high value investigators place on phenotypes observed for genetic perturbation. However, we focus on co-perturbation of ion channel genes and their interacting genetic components as opposed to singly altering ion channel genes in mouse models. This approach will validate our proteomics approaches in the most definitive manner- in vivo. We see in vivo exploration as an essential step to evaluate ion channel function. Our major aims include mapping ion channel interactions and complexes using a high-throughput proteomics platform at UCSF. These data will be interrogated using integrative approaches established by the Monarch Initiative, where biochemical interactions will be validated and prioritized for further study. Another major aim is function-centric: we use mouse models to elucidation of human disease mechanisms, where we embrace a genetic interaction scheme to uncover ion channel redundancy and polygenic effects. Together these integrative approaches complement each other, specifically the in vivo genetic interaction platform interrogates those genes identified from proteomics and bioinformatics analysis. We generate critical reagents and data including antibodies and gene expression patterns. Our broad goal is to identify ion channel phenotypes relevant to fundamental human disease. We bring on board a number of ion channel experts and mouse phenotyping specialists who can accomplish this major programs goals in an efficient manner.

项目摘要 该项目的目标是生成数据和试剂，帮助揭示穷人的关键功能。 离子通道的特征成员。我们优先考虑小鼠模型，考虑到高价值的研究者 对遗传扰动观察到的表型的位置。然而，我们关注的是离子的共同微扰 与单独改变离子通道基因相反， 在小鼠模型中。这种方法将以最明确的方式验证我们的蛋白质组学方法- in vivo.我们认为体内探索是评价离子通道功能的重要步骤。 我们的主要目标包括使用高通量的方法绘制离子通道相互作用和复合物。 蛋白质组学平台。这些数据将使用已建立的综合方法进行查询 由君主倡议，其中生化相互作用将得到验证，并优先考虑进一步 study.另一个主要目标是以功能为中心：我们使用小鼠模型来阐明人类疾病 机制，在那里我们拥抱一个遗传相互作用计划，以揭示离子通道冗余， 多基因效应这些整合方法相互补充，特别是体内 遗传相互作用平台询问那些从蛋白质组学和生物信息学鉴定的基因 分析.我们生成关键试剂和数据，包括抗体和基因表达模式。 我们的主要目标是确定与人类基本疾病相关的离子通道表型。我们带来 在船上的一些离子通道专家和小鼠表型专家谁可以完成这一点， 以高效的方式实现重大目标。