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: 10624675
• 负责人: Kristopher Brannan
• 金额: $ 24.93万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624675
• 关键词: ALS pathology; ALS patients; 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; 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 metabolism; 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.

项目摘要 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定位和翻译和降解的控制。越来越 更多的证据表明，RNA代谢的破坏是许多人类神经退行性疾病的标志， 包括肌萎缩侧索硬化症在内的疾病。了解限制性商业惯例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基础的分子机制的关键。一 由于出现了新类型的与人的RBPs相互作用的RBPs，因此人类RBPs的完整目录是难以捉摸的。 未聚腺苷酸化的前mRNA或缺乏特征性RNA结合结构域的非经典RBP，因此 避免了传统的RNA相互作用组捕获研究。我们开发了一个计算RBP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 用于发现新的RBP类别。该提议试图利用来自该分类器的预测来 实现三大目标。 1.第1阶段：通过疾病相关的非典型RNA结合来确定RNA结合的生物学功能。 核质转运相关候选RBP RANGAP 1。 2.阶段2：确定RNA结合的生物学功能，用于扩大疾病组- 相关的非典型核质转运相关的候选RBP。 3.第二阶段：构建以RBP为中心的蛋白质-蛋白质相互作用网络，扩大人类的谱系 RBP用于表征ALS相关的高阶RNP复合物。 我在DNA和RNA结合蛋白研究方面的丰富经验使我成为 进行这里提出的研究。这些目标将有助于完成一份全面的清单， 人类RBPs将有助于提供RNA调控网络的详细地图。加州大学圣地亚哥分校的Yeo实验室是一个 RNA生物学领域的领导者，因此是执行拟议培训的绝佳环境 建立一个独立的研究项目Yeo实验室位于一个主要的生物医学中心， 研究中心在加州大学圣地亚哥分校，毗邻索尔克研究所，和其他研究机构和生物技术 在拉霍亚的公司。在这里进行拟议中的培训计划将使我有机会接触到STEM领域的领导者 细胞生物学和蛋白质组学的方法，我希望掌握，因为我过渡到独立。