3/3 Integrative Genomic Analysis of Human Brain Development and Autism

3/3 人脑发育和自闭症的综合基因组分析

基本信息

批准号：
9174866
负责人：
MATTHEW W. STATE
金额：
$ 32.36万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-21 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174866
关键词：
Address Adolescence Adult Architecture Area Autistic Disorder Autopsy Bioinformatics Brain Brain Diseases Brain region Cell Nucleus Cells Cerebral cortex ChIP-seq Childhood Chromatin Chromatin Structure Collaborations Collection Complement Complex Corpus striatum structure Data Data Analyses Data Set Development Diagnostic tests Disease Epigenetic Process Etiology Family Fetal Development Fluorescence Functional disorder Gene Expression Gene Expression Regulation Gene Mutation Generations Genes Genetic Genetic Variation Genomics Genotype-Tissue Expression Project Germ Lines Goals Health Heterogeneity Human Impairment Individual Inherited Investigation Lead Link Mental disorders Methodology Molecular Molecular Profiling Mutation Neurons Nuclear Pathway interactions Patients Pattern Phase Prefrontal Cortex Principal Investigator Process Proteins Publications Records Regulatory Element Research Research Personnel Resolution Resources Sorting - Cell Movement Staging Stream Systems Biology Temporal Lobe Time Tissues Transcript Transcriptional Regulation Untranslated RNA Variant Work autism spectrum disorder base biobank brain cell cell type chromatin remodeling developmental neurobiology disorder risk epigenome epigenomics frontal lobe functional genomics genomic data genomic profiles human tissue improved infancy insight interest mind control neurodevelopment neuropsychiatric disorder novel relating to nervous system repetitive behavior risk variant scaffold social communication spatiotemporal statistics tissue/cell culture transcriptome transcriptome sequencing transcriptomics whole genome

项目摘要

ABSTRACT Genetic and genomic investigations have yielded important findings as to the genetic contributions to major psychiatric illnesses, illustrating significant etiological heterogeneity, as well as cross-disorder overlap. It has also become clear that understanding how this genetic variation leads to alterations in brain development and function that underlies psychiatric disease pathophysiology will be greatly advanced by a roadmap of the transcriptomic and epigenetic landscape of the human cerebral cortex across key developmental windows. Here, we propose, via a highly collaborative group of investigators, each with distinct areas of expertise and research focus, to create a scaffold of genomic data for understanding ASD pathophysiology, and psychiatric disorders more broadly. The work proposed here represents an ambitious multi-PI project (Yale, UCLA, and UCSF) that brings together three principal investigators and collaborators with strong publication records and expertise in all approaches necessary to perform this work using state-of-the-art and novel methodologies. We will perform time-, region-, and cell type-specific molecular profiling of control and ASD brains (Aim 1), including RNA-seq based transcriptomics, identifying cis-regulatory elements via ChIP-seq, and use Hi-C to determine the 3D chromatin architecture and physical relationships that underlie transcriptional regulation in three major regions implicated in neuropsychiatric disease (frontal and temporal cortex and striatum) across five major epochs representing disease-relevant stages in human brain development. This will include complementary genomic analyses in controls and matched post mortem ASD brain to identify genetic mechanisms underlying processes altered in ASD brain. We will address cellular heterogeneity via fluorescence-activated nuclear sorting (FANS) so as to profile neurons and non-neural cells separately, which will complement the whole tissue analyses. We will analyze and integrate these datasets to identify regional, developmental, and ASD-related processes to gain insight into underlying mechanisms, harmonizing these multi-omic data with other psychENCODE studies, as well as other large scale data sets, such as BrainSpan, ENCODE, GTEx and Roadmap Epigenomics Project (Aim 2). We will perform integrated analysis of germ-line ASD variations identified in more than 1000 families from the Simons Simplex Collection to characterize causal enrichments in developmental periods, brain regions, and cell types to better characterize the mechanisms by which genetic variation in humans alters brain development and function in health and disease (Aim 3). Completion of these aims will lead to a well-integrated resource across major periods in human cortical and striatal development that will permit generation of concrete testable hypotheses of ASD mechanisms, and inform our pathophysiological understanding of other related neuropsychiatric disorders.

抽象的遗传和基因组研究在遗传对主要疾病的贡献方面取得了重要发现。精神疾病，说明显着的病因异质性以及跨疾病重叠。它有我们还清楚地了解这种遗传变异如何导致大脑发育和大脑发育的改变精神疾病病理生理学的基础功能将通过路线图得到极大的推进人类大脑皮层关键发育窗口的转录组和表观遗传景观。在这里，我们建议，通过一个高度协作的研究小组，每个研究人员都有不同的专业领域和研究重点是创建一个基因组数据支架来理解 ASD 病理生理学和精神病学更广泛的疾病。这里提出的工作代表了一个雄心勃勃的多 PI 项目（耶鲁大学、加州大学洛杉矶分校和 UCSF）汇集了三位具有良好发表记录的主要研究人员和合作者，使用最先进和新颖的方法来执行这项工作所需的所有方法的专业知识。我们将对对照大脑和 ASD 大脑进行时间、区域和细胞类型特异性分子分析（目标 1），包括基于 RNA-seq 的转录组学，通过 ChIP-seq 识别顺式调控元件，并使用 Hi-C 确定转录调控下的 3D 染色质结构和物理关系涉及神经精神疾病的三个主要区域（额叶皮层、颞叶皮层和纹状体）代表人类大脑发育中与疾病相关的阶段的五个主要时期。这将包括对对照和匹配的死后 ASD 大脑进行互补基因组分析，以识别遗传自闭症谱系障碍 (ASD) 大脑中潜在过程改变的机制。我们将通过以下方式解决细胞异质性荧光激活核分选（FANS），以分别分析神经元和非神经细胞，这将补充整个组织分析。我们将分析和整合这些数据集，以确定区域、发育和 ASD 相关过程，以深入了解潜在机制，协调这些过程多组学数据与其他 psychENCODE 研究，以及其他大规模数据集，例如 BrainSpan， ENCODE、GTEx 和路线图表观基因组学项目（目标 2）。我们将对种系进行综合分析从 Simons Simplex Collection 中鉴定出 1000 多个家庭中的 ASD 变异，以表征因果关系丰富发育时期、大脑区域和细胞类型，以更好地表征机制人类的遗传变异会改变健康和疾病中的大脑发育和功能（目标 3）。完成这些目标将导致人类皮质和大脑各主要时期的资源得到良好整合。纹状体发育将允许产生 ASD 机制的具体可检验假设，以及告知我们对其他相关神经精神疾病的病理生理学理解。