ADAR-editing landscape dysregulation in neuropsychiatric disorders

神经精神疾病中 ADAR 编辑景观失调

• 批准号: 10238770
• 负责人: Noel-Marie Plonski
• 金额: $ 2.67万
• 依托单位: KENT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-07-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238770
• 关键词: Accounting; Anxiety; Benchmarking; Binding; Bioinformatics; Brain; Calcium; Cardiovascular Diseases; Cause of Death; Cell Culture Techniques; Cells; Complex; Computer Analysis; Custom; Data; Data Set; Databases; Depression and Suicide; Development; Diagnosis; Economic Burden; Etiology; Frequencies; Fura-2; Genes; Genetic Transcription; Genotype-Tissue Expression Project; Glutamate Receptor; High-Throughput RNA Sequencing; Homeostasis; Human; Image; Immune response; Immune system; Immunohistochemistry; Individual; Innate Immune System; Interferon Activation; Interferon-alpha; Ions; Lead; Link; Major Depressive Disorder; Malignant Neoplasms; Maps; Measures; Mediating; Meta-Analysis; Methods; Molecular; Nervous system structure; Neurologic Symptoms; Neuronal Plasticity; Neurosciences; PF4 Gene; Pathway interactions; Pattern; Permeability; Play; Population; Prefrontal Cortex; Protein Isoforms; Proteins; RNA; RNA Editing; Regulation; Reproducibility; Reproducibility of Results; Research Personnel; Risk; Role; Sampling; Shapes; Signal Transduction; Site; Staging; Suicide; Testing; Training; Translating; United States; Validation; Variant; Virus Diseases; Western Blotting; Work; adenosine deaminase; biomarker discovery; completed suicide; computational pipelines; computerized tools; data visualization; detector; differential expression; disability-adjusted life years; dopaminergic differentiation; excitotoxicity; experience; immune activation; in silico; innate immune pathways; insight; knowledge base; machine learning algorithm; mood regulation; nerve stem cell; nervous system disorder; neurodevelopment; neuropsychiatric disorder; neurotransmission; novel marker; precision medicine; preservation; relating to nervous system; release of sequestered calcium ion into cytoplasm; serotonin receptor; side effect; skills; social; spatiotemporal; suicidal risk; tool; transcriptome; transcriptome sequencing; virtual machine

Project Abstract: Adenosine deaminase acting on RNA (ADAR) editing plays a major role in shaping transcriptome diversity by creating variant isoforms that enable fine-tuning of calcium-mediated excitatory and other signaling needed for brain development, neural plasticity and mood regulation. The spatio-temporal ADAR editing landscapes are tightly regulated by controlling ADAR expression levels to preserve preferential binding and editing. Previous studies have shown that activation of the interferon pathways of the innate immune system – such as those seen in viral infections - leads to increased expression of ADAR1p150, which ultimately results in changes to ADAR editing patterns. Furthermore, common side effects to innate immune activation by interferon alpha therapies include increased risk of depression and suicide. The changes in spatio-temporal regulation of editing patterns can lead to a wide spectrum of neurological symptoms, including neuropsychiatric disorders (e.g., decreased ADAR editing in the serotonin receptor subunit2C in the prefrontal cortex observed in individuals who commit suicide). Yet, our understanding of ADAR editing landscapes remain cursory. Advances in high throughput RNA-seq enable more accurate variant calling from the sequencing reads, providing a way to map ADAR editing patterns in the transcriptome. However, there are no computational pipelines focused on ADAR editing that are easy to use, are reproducible and can handle large scale analysis. I have recently built a pipeline to handle meta-analysis of RNA-seq data that incorporates variant calling steps, but further work is needed to validate this tool to assure accuracy and reproducibility of results. It can then be used to map the spatio-temporal variation of ADAR editing landscapes. The proposed project will study ADAR editing landscapes in the following ways: (i) new computational pipelines will be benchmarked to use variant calling with RNA-seq datasets using simulated reads, (ii) ADAR editing landscape diversity in the publicly available human samples will be mapped; the computational predictions and hypotheses generated from the pipeline will be validated using (iii) measuring calcium flux in cells with known differential ADAR editing landscapes caused by PolyI:C (viral infection mimic) treatment. The proposed work will yield a validated pipeline capable of mapping ADAR editing landscapes with machine learning algorithms. Defining ADAR editing landscapes is paramount to biomarker discovery and can influence precision medicine applications in diagnosis and treatment of neuropsychiatric disorders. This project will allow for me to gain the knowledge base necessary to become an independent researcher with a unique skill set of both computational and benchwork methods to advance the field of neuroscience.

项目摘要： 作用于RNA的腺苷脱氨酶（阿达尔）编辑在转录组的形成中起主要作用 通过创建变体同种型，使钙介导的兴奋性和其他信号转导的微调， 大脑发育、神经可塑性和情绪调节所必需的。时空阿达尔编辑 通过控制阿达尔表达水平来严格调节景观，以保持优先结合， 编辑.先前的研究表明，激活先天免疫系统的干扰素通路- 例如在病毒感染中看到的那些-导致ADAR 1 p150表达增加，最终导致 阿达尔编辑模式的变化。此外，先天免疫激活的常见副作用是 干扰素α治疗包括增加抑郁和自杀的风险。时空的变化 编辑模式的调节可导致广泛的神经系统症状，包括神经精神症状。 疾病（例如，观察到前额叶皮层5-羟色胺受体亚单位2C的阿达尔编辑减少 自杀的人）。然而，我们对阿达尔编辑景观的理解仍然是粗略的。 高通量RNA-seq的进步使得能够从测序读数中更准确地识别变体， 提供了一种在转录组中绘制阿达尔编辑模式的方法。然而，没有计算 专注于阿达尔编辑的流水线易于使用、可再现并且可以处理大规模分析。 我最近建立了一个管道来处理RNA-seq数据的荟萃分析，其中包含变异调用步骤， 但还需要进一步的工作来验证这一工具，以确保结果的准确性和可重复性。然后可以 用于绘制阿达尔编辑景观的时空变化。拟议项目将研究阿达尔 以下列方式编辑景观：（i）将对新的计算管道进行基准测试，以使用变体 调用RNA-seq数据集使用模拟读取，（ii）阿达尔编辑景观多样性在公共 可用的人类样本将被映射;计算预测和假设产生的 将使用（iii）测量具有已知差异阿达尔编辑的细胞中的钙通量来验证管道 PolyI：C（病毒感染模拟）治疗引起的景观。拟议的工作将产生一个有效的 管道能够映射阿达尔编辑景观与机器学习算法。定义阿达尔 编辑景观对生物标志物发现至关重要，并可能影响精准医学应用， 神经精神疾病的诊断和治疗。这个项目将让我获得知识 成为一名独立研究人员所必需的基础， 促进神经科学领域的发展。

项目成果

Automated Isoform Diversity Detector (AIDD): a pipeline for investigating transcriptome diversity of RNA-seq data.

• DOI: 10.1186/s12859-020-03888-6
• 发表时间: 2020-12-30
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Plonski NM;Johnson E;Frederick M;Mercer H;Fraizer G;Meindl R;Casadesus G;Piontkivska H
• 通讯作者: Piontkivska H