Combined brain and gene network approaches to the developmental hypothesis of schizophrenia

大脑和基因网络相结合的精神分裂症发育假说

• 批准号: 10449390
• 负责人: Aaron Felix Alexander-Bloch
• 金额: $ 19.36万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449390
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Age; Anatomy; Area; Autopsy; Base of the Brain; Big Data; Bioinformatics; Biological; Biological Markers; Brain; Brain imaging; Brain region; Candidate Disease Gene; Chronic; Clinical; Communities; Community Networks; Complex; Data; Data Analyses; Data Analytics; Data Set; Development; Disease; Environmental Risk Factor; Epidemiology; Faculty; Freedom; Functional Magnetic Resonance Imaging; Gene Expression; Gene Proteins; Genes; Genetic; Genomic approach; Genomics; Goals; Heritability; Human; Image; Investigation; Leukocytes; Link; Magnetic Resonance Imaging; Mediating; Mental disorders; Mentors; Mentorship; Molecular; National Institute of Mental Health; Nature; Network-based; Pathogenesis; Pathogenicity; Pathology; Pathway Analysis; Pattern; Personality; Phenotype; Process; Proteins; Psychiatry; Psychoses; Psychotic Disorders; Public Domains; Questionnaires; Research; Research Methodology; Research Personnel; Risk; Sampling; Schizophrenia; Schizotypal Personality Disorder; Science; Signal Transduction; Source; Symptoms; Synapses; Techniques; Testing; Thick; Training; Translating; Variant; Work; age effect; brain magnetic resonance imaging; brain tissue; career; clinical phenotype; clinical risk; computerized tools; data integration; developmental disease; experience; functional disability; gene network; genetic variant; genome wide association study; genome-wide analysis; in vivo; insight; member; neurodevelopment; neuroimaging; novel; peripheral blood; phenomics; psychiatric genomics; psychosis risk; risk variant; schizophrenia risk; segregation; synaptic pruning; theories; tool; transcriptomics

PROJECT SUMMARY/ABSTRACT As a computational psychiatry faculty candidate with a strong background in neuroimaging and quantitative data analysis, I seek mentored-support to incorporate genetic and transcriptomic data into my work during my path towards independence as an investigator. I propose a project at the intersection of human neuroimaging, genomics and transcriptomics, using computational tools from network theory to investigate risk for schizophrenia and other forms of chronic psychosis. Prior work suggests that synaptic over-pruning in adolescence disrupts functional and structural connectivity within brain networks, giving rise to symptoms and functional impairments associated with schizophrenia. This process is a product of the interplay of genetic and environmental factors in development, and it is reflected in alterations observed in structural and functional neuroimaging. Network-based analytic approaches allow one to extract deeper insights into the nature of the disturbances in network function, in contrast to simpler attempts to link complex diseases to single brain regions, genes or proteins. The project uses an imaging-genomics approach to test whether networks of genes that are implicated in schizophrenia risk by genome-wide studies of common genetic variants – and have been shown in many cases to be related to synaptic integrity – affect the development of cortical thickness and the functional connections within and between brain networks in typical adolescence. The project also proposes to directly test whether these genetic factors jointly influence these imaging phenotypes and psychosis risk in clinical samples. To meet the research goals of the project, I require formal training in genomics and transcriptomics approaches (and especially their intersection with neuroimaging research). The primary mentorship team (Drs Pearlson and Glahn) has specific expertise in imaging-genomics in clinical datasets, as well as extensive experience as successful research mentors. Other key contributors and consultants provide expertise in imaging-transcriptomics (Dr Holmes), developmental neuroimaging (Dr Satterthwaite), data and network science (Dr Bassett), developmental transcriptomics (Dr Geschwind) and statistical genetics (Dr Blangero). This proposal will provide me with the direct training in research methodology and career support that is required for me to become a fully independent investigator, using tools from neuroimaging, genomics and transcriptomics to investigate psychosis pathogenesis.

项目摘要/摘要 作为具有强大背景神经影像和定量背景的计算精神病学教师 数据分析，我寻求修改支持，将遗传和转录组数据纳入我的工作中 作为研究者的独立之路。我在人类神经影像的交集中提出了一个项目， 基因组学和转录组学，使用网络理论的计算工具来研究 精神分裂症和其他形式的慢性精神病。 先前的工作表明，青少年的突触过度延伸会破坏功能和结构性 大脑网络内的连通性，引起与之相关的符号和功能障碍 精神分裂症。这个过程是遗传和环境因素在发育中的相互作用的产物， 它反映在结构和功能神经影像中观察到的改变。基于网络的分析 方法使人们可以更深入地了解网络功能中灾难的性质，在 与简单的尝试将复杂疾病与单个大脑区域，基因或蛋白质联系起来的尝试形成对比。项目 使用成像基因组学方法来测试精神分裂症中实施的基因网络 全基因组对常见遗传变异的风险 - 在许多情况下已证明与 突触完整性 - 影响皮质厚度的发展以及内部的功能连接 在典型的青少年中的大脑网络之间。该项目还建议直接测试是否 遗传因素共同影响临床样本中这些成像表型和精神病风险。 为了满足项目的研究目标，我需要基因组学和转录组学的正式培训 方法（尤其是它们与神经影像研究的交集）。主要的Mentalship团队（Drs Pearlson和Glahn）在临床数据集中具有成像基因组学方面具有特定的专业知识，并且广泛 作为成功的研究导师的经验。其他关键贡献者和顾问提供专业知识 成像转录组学（Holmes博士），发育神经影像学（Satterthwaite博士），数据和网络 科学（Bassett博士），开发转录组学（Geschwind博士）和统计遗传学（Blangero博士）。 该建议将为我提供研究方法和职业支持的直接培训 我必须使用神经影像学，基因组学和 转录组学研究精神病发病机理。