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）：前额叶皮层（PFC）的功能障碍被认为在精神分裂症的神经生物学中起关键作用。特别是，赤字综合征包括诸如Anhedonia，动机，冷漠和思想含量贫困之类的负面症状，归因于PFC故障。神经营养因子的表达失调，包括脑衍生的神经营养因子（BDNF），以及调节PFC神经元生长和可塑性的其他分子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然不明显。包括microRNA在内的小RNA分子的转录后和翻译调节越来越多地被认为是基因表达和细胞功能的关键控制点。目前，关于microRNA介导的基因表达调节在人类PFC正常发育和包括精神分裂症在内的慢性精神病疾病中的作用尚无。我们的初步数据表明，在PFC锥体神经元中以稳健水平表示，在硅酸盐中预测的MicroRNA与BDNF的3'UTR相互作用的一部分表示，在PFC锥体神经元中构成了BDNF的主要细胞来源，在某些主题（II）中，（II）在PFC中的广泛调节（II）在PFC中受到了（II II）的启动（II II II II II II II II II II）。 精神分裂症。在这些初步发现的指导下，该提案的目标＃1将检查人类前额叶皮层中20多个微洋纳斯的发育调控，层状和细胞表达模式，包括精神分裂症的潜在改变以及抗精神病药的调节。 AIM＃2将进一步探讨用基于慢病毒的转染测定法中RNAi途径在培养的皮质神经元中对BDNF表达的调节。 AIM＃3将使用基于人群遗传学的方法来搜索调节MicroRNA单倍型的BDNF（i）可能赋予精神分裂症和相关疾病的遗传风险，或者（II）影响PFC中microRNA表达的水平。可以预期，将事后研究与动物和细胞培养模型以及临床遗传学相结合的综合建议将对小RNA在正常的前额叶发育和慢性精神病中的作用提供首先见解。公共卫生相关性：精神分裂症是一种主要的精神病，但是我们对潜在的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一个称为microRNA的分子家族。关于这些最近发现的分子对脑功能的重要性知之甚少。我们将研究可能调节神经生长因子蛋白的一部分microRNA，在被诊断为精神分裂症和对照的受试者的死后大脑中，这些研究可能会促进我们对精神分裂症生物学基础的了解，也许可能导致该疾病的新治疗策略的发展。