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: 10248580
• 负责人: Nikolaos mellios
• 金额: $ 28万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248580
• 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.

尽管直到最近还因为不遵守分子生物学的中心教条而被忽视， 非编码RNA(NcRNAs)是一种重要的新型细胞分化调控因子 流程。NcRNAs参与“分子多任务”的能力使它们能够相互连接 多基因人类遗传性疾病的多种遗传风险因素，如精神疾病， 进入正常运行的网络。环状RNAs(CIRC RNAs)是一类新型的非编码RNAs 起源于蛋白质编码的外显子和内含子的反向剪接和共价连接 基因，但缺乏转化为蛋白质的能力。最近的研究表明 CIRC RNA在大脑中丰富，受发育调节，并在 树突和突触。尽管如此，对CIRC RNAs在 哺乳动物大脑及其在自噬和神经精神疾病中的潜在参与。 自噬是细胞降解和再循环的一个协调的溶酶体过程。 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，最近的数据表明，许多人 自噬相关基因在死后脑组织中的表达降低 精神障碍和神经元利用自噬在正常神经元发育和 功能。尽管如此，自噬在精神疾病发病机制中的重要性 其病理生理机制尚未完全阐明。我们建议的研究旨在研究 改变在精神疾病中的作用CIRC RNA来源于自噬相关 基因或是自噬基因表达的上游调节，在神经元自噬和 发展和功能。我特别提出了以下三个目标。目标1：检验假设 精神疾病相关CircRNAs的改变失调线性基因表达 与自噬和神经元的发育和功能有关。目标2：检验假设 操纵精神疾病相关的CIRC RNA不能改变自噬和神经元 发展和功能。目的3：检验通过自噬诱导治疗的假设 药物不能挽救CIRC-NA介导的神经元发育和功能改变。取n 总之，我们提出的研究将阐明这些效应背后的机制 自噬相关的CIRC RNA对神经元A L的自噬和功能，同时平行检测 与精神疾病治疗无关的问题。