Exploring functional complexes and disease networks within human RNA-binding protein interactomes

探索人类 RNA 结合蛋白相互作用组中的功能复合物和疾病网络

• 批准号: 9806758
• 负责人: Kristopher Brannan
• 金额: $ 12.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-10-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806758
• 关键词: Affinity; Alternative Splicing; Amyotrophic Lateral Sclerosis; Binding; Binding Proteins; Biological Process; Biology; Biomedical Research; Biotechnology; C9ORF72; Catalogs; Categories; Cell Nucleus; Cells; Cellular Stress; Code; Complex; Computing Methodologies; Cytoplasm; DNA Binding; Disease; Environment; Gene Expression; Genetic Transcription; Goals; Guanosine Triphosphate Phosphohydrolases; Heart; Human; Institutes; Life Cycle Stages; Maps; Mass Spectrum Analysis; Mediating; Mentors; Metabolism; Methods; Modeling; Molecular; Motor Neurons; Mutate; Neurodegenerative Disorders; Nuclear; Nuclear Pore Complex; Nucleocytoplasmic Transport Proteins; Pathology; Patients; Phase; Phenotype; Post-Transcriptional Regulation; Protein Isoforms; Proteins; Proteomics; Publishing; RAN GTPase Activating Protein 1; RANGAP1 gene; RNA; RNA Binding; RNA Computations; RNA Probes; RNA Recognition Motif; RNA Transport; RNA-Binding Proteins; RNA-Protein Interaction; Reporting; Research; Research Institute; Research Proposals; Resources; Role; Sensitivity and Specificity; Training; Training Programs; Transcript; Translations; Untranslated RNA; Validation; base; experience; experimental study; genome-wide; induced pluripotent stem cell; mRNA Precursor; motor control; mutant; nervous system disorder; nucleocytoplasmic transport; programs; protein protein interaction; stem cell biology; stress granule; transcription factor; transcriptome sequencing

PROJECT SUMMARY RNA binding proteins (RBPs) bind to both coding and non-coding RNA to influence every step of the RNA life- cycle, including pre-mRNA processing, RNA localization, and control of translation and degradation. More and more evidence reveals that disruption of RNA metabolism is a hallmark of many human neurodegenerative diseases including Amyotrophic Lateral Sclerosis. Understanding how RBPs act in coordinated networks to regulate RNA fate is key to uncovering the molecular mechanisms underlying these disease pathologies. A complete catalogue of human RBPs is elusive due to the emergence of new classes of RBPs that interact with unpolyadenylated pre-mRNAs or non-canonical RBPs that lack characterized RNA-binding domains, and thus evade traditional RNA-interactome capture studies. We developed a computational RBP classifier based on the observation that protein-protein interaction networks that depend on co-binding of RNA molecules can be used to discover new classes of RBPs. This proposal seeks to utilize predictions from this classifier to accomplish 3 main goals. 1. Phase 1: Determine the biological function of RNA-binding by the disease-associated non-canonical nucleocytoplasmic transport related candidate RBP RANGAP1. 2. Phase 2: Determine the biological function of RNA-binding for an expanded group of disease- associated non-canonical nucleocytoplasmic transport related candidate RBPs. 3. Phase 2: Build an RBP centered protein-protein interaction network to expand the repertoire of human RBPs to characterize ALS relevant higher order RNP complexes. My extensive experience in the study of DNA and RNA binding proteins makes me an ideal candidate to perform the research proposed here. These aims will build towards the completion of a comprehensive list of human RBPs that will help provide detailed maps of RNA regulatory networks. The Yeo lab at UCSD is a leader in the field of RNA biology, and therefore is an excellent environment to perform the proposed training and build an independent research program. The Yeo lab is situated at the heart of a major biomedical research hub at UCSD, adjacent to the Salk Institute, and other research institutes and biotechnology companies in La Jolla. Conducting the proposed training program here will give me access to leaders in stem cell biology and proteomic methods that I hope to master as I transition to independence.

项目概要 RNA 结合蛋白 (RBP) 与编码和非编码 RNA 结合，影响 RNA 生命的每一步 - 循环，包括前 mRNA 加工、RNA 定位以及翻译和降解的控制。更多和 更多证据表明 RNA 代谢的破坏是许多人类神经退行性疾病的标志 疾病包括肌萎缩侧索硬化症。了解 RBP 如何在协调网络中发挥作用 调节RNA命运是揭示这些疾病病理背后的分子机制的关键。一个 人类 RBP 的完整目录是难以捉摸的，因为新类别的 RBP 的出现与相互作用 非多聚腺苷酸化的前 mRNA 或非典型 RBP 缺乏特征性的 RNA 结合结构域，因此 逃避传统的 RNA 相互作用组捕获研究。我们开发了一个基于 RBP 的计算分类器 观察到依赖于 RNA 分子共结合的蛋白质-蛋白质相互作用网络可以 用于发现新类别的 RBP。该提案旨在利用该分类器的预测来 实现 3 个主要目标。 1. 第 1 阶段：通过疾病相关的非典型物质确定 RNA 结合的生物学功能 核细胞质运输相关候选 RBP RANGAP1。 2. 第 2 阶段：确定 RNA 结合对扩大的疾病组的生物学功能 - 相关的非规范核细胞质运输相关的候选 RBP。 3. 第二阶段：建立以 RBP 为中心的蛋白质-蛋白质相互作用网络，以扩展人类的功能库 RBP 用于表征 ALS 相关的高阶 RNP 复合体。 我在 DNA 和 RNA 结合蛋白研究方面的丰富经验使我成为以下领域的理想人选： 执行此处提出的研究。这些目标将致力于完成一份全面的清单 人类 RBP 将有助于提供 RNA 调控网络的详细图谱。 UCSD 的 Yeo 实验室是 RNA 生物学领域的领导者，因此是进行拟议培训的绝佳环境 并建立一个独立的研究计划。 Yeo 实验室位于主要生物医学中心的中心 加州大学圣地亚哥分校的研究中心，毗邻索尔克研究所以及其他研究机构和生物技术 拉霍亚的公司。在这里进行拟议的培训计划将使我有机会接触到科学领域的领导者 我希望在过渡到独立时能够掌握细胞生物学和蛋白质组学方法。