DNA methylation as a mechanism for reduced dendritic spine density in schizophrenia - Supplement

DNA 甲基化作为精神分裂症树突棘密度降低的机制 - 补充

• 批准号: 10379529
• 负责人: Brandon C McKinney
• 金额: $ 5.57万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379529
• 关键词: Affect; Auditory Hallucination; Autopsy; Brain; Brain region; CRISPR/Cas technology; Candidate Disease Gene; Cytosine Nucleotides; DNA Methylation; Dendritic Spines; Development; Epigenetic Process; Functional disorder; Funding; Genes; Genetic Code; Genetic Transcription; Genome; Impairment; Measures; Mediating; Mental disorders; Mentored Patient-Oriented Research Career Development Award; Modification; Neurons; Nuclear Pore Complex; Pathology; Rattus; Regulation; Regulator Genes; Research Personnel; Research Project Grants; Research Training; Role; Schizophrenia; Site; Superior temporal gyrus; Symptoms; System; Testing; Therapeutic Uses; Training; Transcript; United States National Institutes of Health; auditory processing; base; behavior observation; clinical investigation; clinically relevant; cohort; density; genome-wide; innovation; methyl group; multidisciplinary; social cognition; therapeutic target

7. Project Summary/Abstract - no change from original. Schizophrenia (SZ) is a devastating psychiatric disorder with limited treatment options. Disruptions in cortical circuitry are a key feature of SZ pathology and pathophysiology. Reduced dendritic spine density (DSD) in cortical layer 3 is among the most consistently observed cortical circuit abnormalities in postmortem studies of SZ, affecting multiple brain regions including the superior temporal gyrus (STG). Reduced DSD is thought to underlie multiple symptom domains in SZ including auditory processing deficits that impair social cognition and auditory hallucinations, however, the mechanisms that contribute to reduced DSD are poorly understood. DNA methylation (DNAm), the addition of a methyl group to a cytosine nucleotide, is a regulator of gene transcription. Given that (1) DNAm is altered in the brains of SZ subjects and (2) DNAm is altered in other contexts characterized by DSD abnormalities, DNAm is a strong candidate mechanism for reduced DSD in SZ. Despite evidence suggesting a role for DNAm in regulation of DSD, the relationship between DNAm and reduced DSD in SZ has not previously been explored. We propose studies to test the hypothesis that reduced DSD in SZ results, in part, from the altered transcription of multiple genes caused by alterations in DNAm. First, we will assess genome-wide, site-specific DNAm selectively in layer 3 of STG in a large SZ-NPC cohort for which DSD has already been characterized. Then, we will hone in on the DNAm-DSD correlations, and the DNAm-gene transcription relationships that may mediate those correlations, in STG layer 3 PYR neurons. Finally, we will test the causal relationship between DNAm and DSD by using the CRISPR/Cas9 system to alter candidate gene DNAm in a genome-region-specific manner and measure DSD in neuron cultures. To compliment this research project, I have developed an innovative, comprehensive, and multidisciplinary training plan to facilitate my transition to independent investigator. Upon completion of the proposed research and training plans, I will be an expert in psychiatric epigenetics, generally, and in applying cutting-edge approaches to the study of dendritic spine pathology in SZ, specifically. Few researchers have the necessary background and training to connect the multiple levels of investigation— clinical observation/behavior, circuits, neurons, transcript expression, epigenetic modifications, and genetic code—necessary to make innovative and clinically-relevant contributions to understanding the epigenetic mechanisms of psychiatric disorders. It is with this unique combination of background and training, that I will establish my independent, NIH-funded lab and submit for R01 funding in year 3 of my K23 award period.

7。项目摘要/摘要 - 与原件无更改。 精神分裂症（SZ）是一种毁灭性的精神病，治疗方案有限。皮质的干扰 电路是SZ病理学和病理生理学的关键特征。减少树突状脊柱密度（DSD） 皮质层第3层是最一致观察到的皮质回路异常之一 SZ，影响包括上临时回（STG）在内的多个大脑区域。减少DSD被认为 SZ中多个症状领域的基础包括听觉处理，定义了损害社会认知和 然而，听觉幻觉，促成减少DSD的机制知之甚少。脱氧核糖核酸 甲基化（DNAM）是在胞嘧啶核苷酸中添加甲基，是基因转录的调节剂。 鉴于（1）DNAM在SZ受试者的大脑中发生了变化，并且（2）DNAM在其他情况下发生了变化 DNAM以DSD异常为特征，是SZ中DSD降低的强大候选机制。尽管 证据表明DNAM在调节DSD中的作用，DNAM与DSD降低的关系 以前尚未探讨在SZ中。我们提出的研究测试了降低SZ中DSD的假设 结果部分是由于DNAM改变引起的多个基因转录的改变。 首先，我们将在大型SZ-NPC队列中选择性地评估STG第3层的全基因组特异性DNAM DSD已经被描述了。然后，我们将磨练DNAM-DSD相关性，并磨练 DNAM-GENE转录关系可能会介导这些相关性，在STG层3 pyr神经元中。 最后，我们将通过使用CRISPR/CAS9系统更改DNAM和DSD之间的因果关系 候选基因DNAM的基因组区域特异性方式，并测量神经元培养物中的DSD。到 称赞这个研究项目，我开发了一种创新，全面和多学科的培训 计划促进我向独立调查员的过渡。 拟议的研究和培训计划完成后，我将成为精神病学专家， 通常，在采用尖端方法来研究SZ中的树突状脊柱病理学时，特别是。 很少有研究人员拥有必要的背景和培训来连接多个投资水平 - 临床观察/行为，电路，神经元，转录本表达，表观遗传修饰和遗传 代码 - 有必要为理解表观遗传学做出创新和临床上的贡献 精神疾病的机制。正是这种背景和培训的独特组合，我将 建立我的独立NIH资助的实验室，并在我的K23奖励期的第3年提交R01资金。