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

基本信息

批准号：
10019808
负责人：
Aaron Felix Alexander-Bloch
金额：
$ 16.79万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
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/10019808
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 Psychotic Disorders Public Domains Questionnaires Research Research Methodology Research Personnel Risk Sampling Schizophrenia Schizotypal Personality Disorder Science Signal Transduction Source Structure Symptoms Synapses Techniques Testing Thick Training Translating Variant Work age effect brain tissue career clinical phenotype clinical risk computerized tools data integration developmental disease experience functional disability genetic variant genome wide association study genome-wide analysis in vivo insight member neurodevelopment neuroimaging novel peripheral blood phenomics risk variant segregation synaptic pruning theories tool transcriptomics

项目摘要

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.

项目概要/摘要作为一名计算精神病学教师候选人，具有很强的神经影像和定量背景数据分析期间，我寻求指导支持，将遗传和转录组数据纳入我的工作中我提出了一个关于人类神经影像学交叉点的项目，基因组学和转录组学，使用网络理论的计算工具来研究风险精神分裂症和其他形式的慢性精神病。先前的研究表明，青春期的突触过度修剪会破坏功能和结构大脑网络内的连接，引起与以下相关的症状和功能障碍这个过程是发育过程中遗传和环境因素相互作用的产物。它反映在基于网络的分析中观察到的结构和功能的变化。这些方法使人们能够更深入地了解网络功能中扰动的本质，与将复杂疾病与单个大脑区域、基因或蛋白质联系起来的简单尝试相反。使用成像基因组学方法来测试是否与精神分裂症有关的基因网络对常见遗传变异进行全基因组研究得出的风险 - 并且在许多情况下已被证明是相关的突触完整性——影响皮质厚度的发育以及内部的功能连接该项目还建议直接测试这些是否存在于典型青春期的大脑网络之间。遗传因素共同影响临床样本中的这些成像表型和精神病风险。为了实现该项目的研究目标，我需要基因组学和转录组学方面的正式培训主要指导团队（博士）。 Pearlson 和 Glahn）在临床数据集中的成像基因组学方面拥有特定的专业知识，以及广泛的作为成功的研究导师的经验。其他主要贡献者和顾问提供了以下方面的专业知识。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）、发育转录组学（Geschwind 博士）和统计遗传学（Blangero 博士）。该提案将为我提供研究方法和职业支持方面的直接培训我需要成为一名完全独立的研究者，使用神经影像学、基因组学和转录组学研究精神病发病机制。