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Modified RNA tools and diagnostics for drug abuse

改良 RNA 工具和药物滥用诊断

基本信息

批准号：
8841583
负责人：
PAUL F AGRIS
金额：
$ 22.5万
依托单位：
ATHGHIN BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8841583
关键词：
Adopted Affect Anterior Biological Biological Assay Biological Markers Biological Process Brain Cannabinoids Cell physiology Cells Cerebral cortex Chemical Exposure Chemicals Chemistry Chronic Communities Complex Computer software Cues Detection Development Diagnostic Disease Drug Exposure Drug abuse Epigenetic Process Functional RNA Gene Expression Gene Expression Regulation Goals Health High Pressure Liquid Chromatography Human Investigation Legal Liquid substance Mass Spectrum Analysis Measures Mental disorders Messenger RNA Metabolic Methods Methylation Modification Molecular Nervous system structure Neuroglia Neurons Nicotine Nucleosides Pathology Pattern Pharmaceutical Preparations Play Prosencephalon RNA RNA Degradation RNA Stability Reporting Research Resolution Role Sample Size Specificity Speed Staging Structure Substance abuse problem Substance of Abuse Technical Expertise Technology Testing abstracting analytical method base biological systems brain cell computerized data processing drug of abuse induced pluripotent stem cell insight instrumentation liquid chromatography mass spectrometry nervous system disorder novel public health relevance tool

项目摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract RNA modifications are numerous, and range from simple methylation to complex changes such as addition of aminoacylcarbamoyl moieties. These modifications and, the levels at which are present, are emerging as important regulators of biological processes, and perturbations such as chemical or drug exposure can alter the patterns of specific modifications on RNA sub-types. Moreover, given their variety, specificity and their relationship to function and structure stability, RNA modifications are potentially valuable biomarkers of disease and treatment progression, especially given that modified nucleosides are relatively stable even after RNA degradation, and can be released from cells into bodily fluids. The long term objective of this study is to facilitae research into RNA modifications and their impact on health and disease. The immediate hurdle, and the goal of this application, is to develop extremely sensitive analytical methods for detection and quantification of common and novel RNA modifications that can be readily disseminated to the RNA research community. The test case biological system is based on human induced pluripotent stem cell derived nervous system cells that will be exposed to two different drugs of abuse, nicotine and cannabinoids. Aim 1. We will use RNA modified nucleoside standards to develop highly sensitive and robust method of analysis. The ultimate tool we will be developing is a product resultant from the combination of two technologies, UHPLC and MS that will be optimized for high resolution separation and highly sensitive detection of RNA modifications. The tools developed will be tested on differentiated anterior cerebral cortex neurons and glia cells and RNA modifications will be characterized and abundances quantified during the different stages of maturation. Aim 2. Tools developed during aim 1 will be further adapted to detect specific RNA modifications that may be playing a significant role on differentiated forebrain cells, as a result from treatment with drug of abuse. During this aim we will specifically study forebrain cells that will be exposed to different nicotie and cannabinoids concentrations and compared to vehicle controls. The results of the methods we are proposing will be in the form of highly sensitive and accurate tools for the analysis of a wide range of chemistries and abundances of RNA modifications present in regulatory RNAs. The ultimately goal is to develop highly sensitive RNA modifications-based biomarkers discovery tools that requires minimal level of technical expertise as a way to disseminate and accelerate the field of RNA modifications with regards to gain further insight into mechanisms of disease.

描述（由申请人提供）：项目摘要/摘要RNA修饰有很多种，范围从简单的甲基化到复杂的变化，如添加氨酰基氨基甲酰基部分。这些修饰和存在的水平正在成为生物过程的重要调节剂，并且诸如化学或药物暴露的扰动可以改变RNA亚型上的特定修饰的模式。此外，鉴于其多样性、特异性及其与功能和结构稳定性的关系，RNA修饰是疾病和治疗进展的潜在有价值的生物标志物，特别是鉴于修饰的核苷即使在RNA降解后也相对稳定，并且可以从细胞释放到体液中。这项研究的长期目标是促进对RNA修饰及其对健康和疾病影响的研究。直接的障碍，以及本申请的目标，是开发用于检测和定量常见和新型RNA修饰的非常灵敏的分析方法，这些方法可以很容易地传播到RNA研究界。测试用例生物系统基于人类诱导多能干细胞衍生的神经系统细胞，这些细胞将暴露于两种不同的滥用药物，尼古丁和大麻素。目标1.我们将使用RNA修饰的核苷标准品来开发高灵敏度和稳健的分析方法。我们将开发的最终工具是UHPLC和MS两种技术相结合的产物，该产品将针对RNA修饰的高分辨率分离和高灵敏度检测进行优化。开发的工具将在分化的前大脑皮层神经元和神经胶质细胞上进行测试，RNA修饰将在成熟的不同阶段进行表征和丰度量化。目标二。在目标1期间开发的工具将进一步适用于检测特定的RNA修饰，这些修饰可能对分化的前脑细胞起重要作用，这是滥用药物治疗的结果。在此期间，我们将专门研究前脑细胞，这些细胞将暴露于不同的尼古丁和大麻素浓度，并与溶剂对照进行比较。我们提出的方法的结果将是高度灵敏和准确的工具，用于分析调节RNA中存在的广泛的RNA修饰的化学性质和丰度。最终目标是开发高度敏感的基于RNA修饰的生物标志物发现工具，该工具需要最低水平的技术专业知识，作为传播和加速RNA修饰领域的一种方式，以进一步深入了解疾病的机制。