Illuminating Druggable Dark Matter

项目摘要 这个项目的目标是生成数据和试剂，帮助揭示穷人的关键功能 表征了离子通道的成员。我们优先考虑老鼠模型，考虑到高价值的研究人员 放置在观察到的遗传扰动的表型上。然而，我们关注的是离子的协同微扰。 通道基因及其相互作用的遗传成分，而不是单一改变离子通道基因 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- 在活体内。我们认为体内探索是评估离子通道功能的必要步骤。 我们的主要目标包括使用高通量的 加州大学旧金山分校的蛋白质组学平台。这些数据将使用建立的综合方法进行询问 通过君主倡议，生物化学相互作用将得到验证并确定优先顺序，以便进一步 学习。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，其中我们采用遗传交互方案来揭示离子通道冗余和 多基因效应。这些综合方法结合在一起是相辅相成的，特别是体内 基因相互作用平台询问那些从蛋白质组和生物信息学中鉴定出来的基因 分析。我们生成关键试剂和数据，包括抗体和基因表达模式。 我们的广泛目标是确定与人类基础疾病相关的离子通道表型。我们带来了 船上有许多离子通道专家和老鼠表型鉴定专家，他们可以做到这一点 以有效的方式实现主要计划的目标。

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.