Role of circular RNAs in autophagy regulation and neuronal development and function in psychiatric disorders

环状RNA在精神疾病中自噬调节以及神经元发育和功能中的作用

• 批准号: 10249124
• 负责人: Nikolaos mellios
• 金额: $ 28.05万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249124
• 关键词: Autophagocytosis; Autopsy; Back; Brain; Categories; Cell physiology; Code; Data; Dendrites; Development; Disease; Functional disorder; Gene Expression; Genes; Genetic Diseases; Human Genetics; Inflammation; Joining Exons; Link; Mediating; Mental disorders; Metabolism; Molecular; Molecular Biology; Neurodegenerative Disorders; Neurons; Organelles; Pathogenesis; Pharmaceutical Preparations; Positioning Attribute; Process; Proteins; RNA; RNA Splicing; Recycling; Regulation; Research; Role; Synapses; Testing; Therapeutic; Translating; Untranslated RNA; circular RNA; genetic risk factor; intein; multitask; neuron development; novel; protein aggregation

Although ignored until recently for not complying with the central dogma of molecular biology, non-coding RNAs (ncRNAs) are emerging as important novel regulators of diverge cellular processes. The capacity of ncRNAs to engage in "molecular multitasking" positions them to link multiple genetic risk factors for polygenic human genetic disorders, such as psychiatric diseases, into functional networks. Circular RNAs (circ RNAs) are a novel category of non-coding RNAs that are derived from the back-splicing and covalent joining of exons and introns of protein-coding genes, yet lack the capacity to become translated into protein. Recent studies have suggested that circ RNAs are enriched in the brain, are developmentally regulated, and are abundant in dendrites and synapses. Despite this, nothing is known about the function of circ RNAs in the mammalian brain and their potential involvement in autophagy and neuro psychiatric disease. Autophagy is a coordinated lysosomal process for the degradation and recycling of cellular components, organelles, and protein aggregates that has been heavily implicated in the pathophysiology of neurodegenerative disorders. However, recent data suggest that numerous autophagy-associated genes display reduced expression in postmortem brains of subjects with psychiatric disorders and that neurons utilize autophagy during normal neuronal development and function. Despite the above, the importance of autophagy in psychiatric disease pathogenesis and pathophysiology has not been fully elucidated. Our proposed research aims in examining the role of altered in psychiatric disorders circ RNAs that are either derived from autophagy-related genes or are upstream regulators of autophagy gene expression in neuronal autophagy and development and function. I specifically propose the following 3 aims. Aim 1: Test the hypothesis that alterations in psychiatric disease-associated circRNAs dysregulate linear gene expression related to autophagy and neuronal development and function. Aim 2: Test the hypothesis that manipulation of psychiatric disease-related circ RNAs ca n alter autophagy and neuronal development and function. Aim 3: Test the hypothesis that treatment with autophagy- inducing drugs ca n rescue circ R NA- mediated alterations in neuronal development and function. Take n together our proposed research will elucidate the mechanisms that underlie the effects of autophagy-associated circ RNAs on neuron a l autophagy and function, while examining in parallel the irrelevance for psychiatric disease therapeutics.

虽然直到最近才因不遵守分子生物学的中心法则而被忽视， 非编码RNA（ncRNA）是新兴的重要的新的调节分化的细胞 流程. ncRNA参与“分子多任务”的能力使它们能够连接 多基因人类遗传疾病的多种遗传风险因素，如精神疾病， 功能网络。环状RNA（circular RNA）是一类新的非编码RNA， 是由编码蛋白质的外显子和内含子的反向剪接和共价连接而成的。 基因，但缺乏翻译成蛋白质的能力。最近的研究表明 circRNA在大脑中富集，受到发育调节，并且在大脑中丰富。 树突和突触。尽管如此，关于circRNA在细胞中的功能还一无所知。 哺乳动物脑及其在自噬和神经精神疾病中的潜在参与。 自噬是一个协调的溶酶体过程，用于细胞内的降解和再循环。 成分，细胞器和蛋白质聚集体，这些都与 神经退行性疾病的病理生理学。然而，最近的数据显示， 自噬相关基因在患有脑梗死的受试者死后大脑中的表达减少， 神经元在正常神经元发育期间利用自噬， 功能尽管如此，自噬在精神疾病发病机制中的重要性 病理生理学尚未完全阐明。我们建议的研究旨在研究 在精神疾病中改变的circ RNA的作用， 或者是神经元自噬中自噬基因表达的上游调节因子， 发展和功能。我具体提出以下三个目标。目标1：检验假设 精神疾病相关circRNA的改变会使线性基因表达失调， 与自噬和神经元发育和功能有关。目标2：检验假设， 操纵精神疾病相关的circRNA可以改变自噬和神经元 发展和功能。目的3：检验用自噬诱导的细胞因子治疗 药物可以挽救circ RNA介导的神经元发育和功能的改变。拿n 我们提出的研究将共同阐明 自噬相关的circ RNA对神经元自噬和功能的影响， 与精神疾病治疗无关