Small RNA regulation of BDNF expression in schizophrenia

精神分裂症中 BDNF 表达的小 RNA 调控

• 批准号: 7648094
• 负责人: Schahram Akbarian
• 金额: $ 36.3万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648094
• 关键词: 3' Untranslated Regions; Adult; Affect; Age; Anhedonia; Animals; Antipsychotic Agents; Autistic Disorder; Autopsy; Biological; Biological Assay; Bipolar Depression; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cell Culture Techniques; Cell physiology; Cerebral cortex; Childhood; Chronic; Clinical; Collection; Comparative Study; Computer Simulation; Conserved Sequence; Controlled Study; Data; Development; Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Family; Functional disorder; Gene Expression; Gene Expression Regulation; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Growth; Haplotypes; Histocytochemistry; Human; Human Development; Immunoblotting; In Situ Hybridization; Individual; Knowledge; Lasers; Lead; Left; Measures; Mediating; Mental disorders; Messenger RNA; MicroRNAs; Microdissection; Modeling; Molecular Biology; Monitor; Mood stabilizers; Mus; Mutation; Nerve Growth Factors; Neurobiology; Neuronal Differentiation; Neurons; Pathway interactions; Pattern; Pharmaceutical Preparations; Play; Population Genetics; Positioning Attribute; Poverty; Prefrontal Cortex; Pregnancy Trimesters; Prosencephalon; Proteins; RNA Interference; Rattus; Regulation; Research Project Grants; Role; Schizophrenia; Signal Transduction; Small RNA; Source; Specimen; Subfamily lentivirinae; Symptoms; Time; Transfection; Translational Regulation; Variant; base; case control; cohort; deficit syndrome; hippocampal pyramidal neuron; insight; mRNA Stability; molecular pathology; nerve stem cell; neuronal growth; neurotrophic factor; prenatal; protein expression; public health relevance; solution hybridization; treatment strategy

DESCRIPTION (provided by applicant): Dysfunction of the prefrontal cortex (PFC) is thought to play a key role in the neurobiology of schizophrenia. In particular, the deficit syndrome which includes negative symptoms such as anhedonia, amotivation, apathy and poverty of thought content, is attributed to PFC malfunction. Dysregulated expression of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), and other molecules regulating neuronal growth and plasticity in PFC may contribute to impaired cellular functions in schizophrenia, but the underlying molecular pathology remains unclear. Post-transcriptional and translational regulation by small RNA molecules, including microRNAs, is increasingly recognized as a key control point of gene expression and cellular functions. Presently, nothing is known about the role of microRNA-mediated regulation of gene expression during normal development of the human PFC and in chronic psychiatric disease conditions, including schizophrenia. Our preliminary data show that a subset of microRNAs predicted in silico to interact with the 3'UTR of BDNF are (i) expressed at robust levels in PFC pyramidal neurons, which comprise the primary cellular source of BDNF in cerebral cortex, (ii) are dynamically regulated during the extended course of PFC maturation and (iii) potentially dysregulated in some subjects diagnosed with schizophrenia. Guided by these preliminary findings, Aim #1 of this proposal will examine the developmental regulation and laminar and cellular expression pattern of over 20 microRNAs in human prefrontal cortex, including potential alterations in schizophrenia and regulation by antipsychotic drugs. Aim #2 will further explore the regulation of BDNF expression by the RNAi pathway in cultured cortical neurons with lentivirus-based transfection assays. Aim #3 will use a population genetics-based approach to search for BDNF regulating microRNA haplotypes that (i) might confer genetic risk for schizophrenia and related disease or (ii) affect levels of microRNA expression in PFC. It is expected that this integrative proposal, which combines postmortem studies with animal and cell culture models and clinical genetics, will provide first insights into the role of small RNAs for normal prefrontal development and chronic psychiatric disease. PUBLIC HEALTH RELEVANCE: Schizophrenia is a major psychiatric disease, but our understanding of the underlying molecular biology and genetics remains incomplete. This research project is focused on a family of molecules called microRNAs . Very little is known about the importance of these recently discovered molecules for brain functions. We will study a subset of microRNAs that might regulate a nerve growth factor protein, in postmortem brain of subjects diagnosed with schizophrenia and controls, these studies might advance our knowledge on the biological basis of schizophrenia, and perhaps, may lead to the development of new treatment strategies for the disorder.

描述（由申请人提供）：前额皮质（PFC）功能障碍被认为在精神分裂症的神经生物学中发挥着关键作用。特别是，包括消极症状（例如快感缺乏、缺乏积极性、冷漠和思想内容贫乏）的赤字综合症归因于前额叶皮层（PFC）功能障碍。神经营养因子（包括脑源性神经营养因子（BDNF））和其他调节 PFC 中神经元生长和可塑性的分子的表达失调可能导致精神分裂症的细胞功能受损，但潜在的分子病理学仍不清楚。小RNA分子（包括microRNA）的转录后和翻译调节越来越被认为是基因表达和细胞功能的关键控制点。目前，对于 microRNA 介导的基因表达调节在人类 PFC 正常发育过程中以及在慢性精神疾病（包括精神分裂症）中的作用尚不清楚。我们的初步数据表明，在计算机中预测与 BDNF 3'UTR 相互作用的 microRNA 子集 (i) 在 PFC 锥体神经元中以稳定水平表达，这些神经元构成大脑皮层 BDNF 的主要细胞来源，(ii)在 PFC 成熟的延长过程中动态调节，并且 (iii) 在一些诊断为精神分裂症的受试者中可能失调。在这些初步发现的指导下，该提案的目标#1将检查人类前额皮质中20多种microRNA的发育调节以及层状和细胞表达模式，包括精神分裂症的潜在改变和抗精神病药物的调节。目标#2 将通过基于慢病毒的转染测定进一步探索培养的皮质神经元中 RNAi 途径对 BDNF 表达的调节。目标 #3 将使用基于群体遗传学的方法来寻找 BDNF 调节 microRNA 单倍型，这些单倍型 (i) 可能会带来精神分裂症和相关疾病的遗传风险，或 (ii) 影响 PFC 中 microRNA 的表达水平。这项综合提案将尸检研究与动物和细胞培养模型以及临床遗传学相结合，预计将为小RNA在正常前额叶发育和慢性精神疾病中的作用提供初步见解。公共卫生相关性：精神分裂症是一种主要的精神疾病，但我们对潜在分子生物学和遗传学的理解仍然不完整。该研究项目的重点是称为 microRNA 的分子家族。人们对这些最近发现的分子对大脑功能的重要性知之甚少。我们将在被诊断为精神分裂症的受试者和对照组的死后大脑中研究可能调节神经生长因子蛋白的 microRNA 子集，这些研究可能会增进我们对精神分裂症生物学基础的了解，也许可能会导致新的治疗方法的开发。该疾病的治疗策略。