Retrotransposons in Schizophrenia

精神分裂症中的反转录转座子

• 批准号: 8703800
• 负责人: Wade H Berrettini
• 金额: $ 20万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-18 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703800
• 关键词: Adolescence; Affect; Alleles; Attenuated; Autopsy; Behavior; Biological Assay; Brain; Brain Diseases; Cardiovascular Diseases; Cell physiology; Cells; Chronic; Cognitive; Copy Number Polymorphism; DNA; Data; Daughter; Delusions; Detection; Development; Disease; Electroencephalography; Elements; Embryonic Development; Event; Family Study; Functional disorder; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Hallucinations; Heritability; High-Throughput Nucleotide Sequencing; Human Genome; Individual; Inherited; Interneurons; Introns; Junk DNA; Life Expectancy; Long Interspersed Nucleotide Elements; Luciferases; Morbidity - disease rate; Mosaicism; Mutation; Neurodevelopmental Disorder; Neuronal Differentiation; Neurons; Odds Ratio; Organism; Parvalbumins; Paste substance; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Population; Prefrontal Cortex; Psychotic Disorders; Public Health; Pyramidal Cells; RNA; RNA-Directed DNA Polymerase; Regulation; Reporter; Rest; Retrotransposon; Risk; Sample Size; Schizophrenia; Source; Suicide; Symptoms; Testing; Tissues; Twin Studies; Variant; Withdrawal; base; disability; disorder risk; endonuclease; gene function; genome wide association study; hippocampal pyramidal neuron; improved; laser capture microdissection; mortality; neuroimaging; novel; promoter; public health relevance; research study; social; solution hybridization; transposon/insertion element

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a common, chronic group of psychotic brain disorders, affecting 1% of the US population, creating a significant public health problem because of the associated disability, morbidity and mortality. The pathogenesis of SZ is poorly understood, but it is thought to be a neurodevelopmental disorder. Neuroimaging evidence has accumulated to indicate that the dorsolateral prefrontal cortex functions abnormally in SZ, both when activated and at rest. Further, EEG evidence has identified abnormalities of ¿ oscillations in SZ, suggesting that parvalbumin positive GABAergic interneuron regulation of cortical pyramidal neurons is dysfunctional. In the past 5 years, data have accumulated to prove that neuronal embryogenesis is accompanied by activation of LINE1 (L1) retrotransposons (RTPs) to an unexpected degree, such that each developing neuron may accumulate multiple de novo L1 RTP genomic insertions, perhaps as many as ~80. This results in a substantial mosaicism within populations of CNS neurons. While most of these somatic de novo L1 RTP insertions will have little effect on neuronal function (perhaps because they occur in gene deserts or in large introns or in genes not required for that cell's function), some may interfere with normal neuronal activity because they have inserted into a gene needed by that particular neuron for normal function. If one or more functional L1 RTP insertion events occur early in CNS development, all the daughter neurons that derive from that neuronal precursor will also carry the L1 insertion, perhaps leading to a dysfunctional population of neurons destined to increase risk for SZ. This proposal will employ CNS tissue (obtained at autopsy) from SZ patients and matched controls. Using laser capture microdissection of parvalbumin positive interneurons and their target pyramidal cells of dorsolateral prefrontal cortex, followed by high-throughput sequencing, detection of novel L1 RTP insertions will be accomplished. In this manner, it is expected that novel somatic L1 RTP insertions, which increase risk for SZ, will be discovered.

描述（由申请人提供）：精神分裂症 (SZ) 是一种常见的慢性精神性脑部疾病，影响 1% 的美国人口，由于相关的残疾、发病率和死亡率而造成严重的公共健康问题。 SZ 的发病机制尚不清楚，但它被认为是一种神经发育障碍。神经影像学证据表明，SZ 中的背外侧前额皮质功能异常，无论是激活时还是休息时。此外，EEG 证据已发现 SZ 振荡异常，表明皮质锥体神经元的小白蛋白阳性 GABA 能中间神经元调节功能失调。在过去的5年里，积累的数据证明神经元胚胎发生伴随着LINE1（L1）逆转录转座子（RTP）的激活到意想不到的程度，使得每个发育中的神经元可能积累多个从头L1 RTP基因组插入，可能多达约80个。这导致中枢神经系统神经元群体内出现大量嵌合现象。虽然大多数体细胞从头 L1 RTP 插入对神经元功能几乎没有影响（可能是因为它们发生在基因荒漠或大内含子或细胞功能不需要的基因中），但有些可能会干扰正常神经元活动，因为它们插入了特定神经元正常功能所需的基因。如果在 CNS 发育早期发生一个或多个功能性 L1 RTP 插入事件，则源自该神经元前体的所有子神经元也将携带 L1 插入，可能会导致神经元群体功能失调，从而增加 SZ 的风险。该提案将使用来自 SZ 患者和匹配对照的 CNS 组织（在尸检中获得）。利用激光捕获显微切割小清蛋白阳性中间神经元及其背外侧前额叶皮质的目标锥体细胞，然后进行高通量测序，将完成新型 L1 RTP 插入的检测。通过这种方式，预计会发现增加 SZ 风险的新型体细胞 L1 RTP 插入。