Developmental GTEx Laboratory, Data Analysis and Coordination Center

GTEx发展实验室、数据分析与协调中心

基本信息

批准号：
10662497
负责人：
KRISTIN ARDLIE
金额：
$ 311.62万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662497
关键词：
21 year old ATAC-seq Adolescence Adult Affect Age Anatomy Autopsy Biological Assay Biology Brain Cell model Cells Cellular Assay Childhood Collaborations Communities Compensation Complex Computational Biology Computing Methodologies Consent Data Data Analyses Development Developmental Process Disease Disease susceptibility Elements Ensure Epigenetic Process Gene Expression Genes Genetic Genetic Diseases Genetic Transcription Genetic Variation Genome Genomics Genotype-Tissue Expression Project Goals Heart Human Human Cell Line Human Development Human Genetics Immune Individual Investments Laboratories Link Logistics Lung Maps Masks Measures Mediation Methods Modeling Molecular Molecular Profiling Multiomic Data Nucleic Acid Regulatory Sequences Process Production Protocols documentation Proxy Quantitative Trait Loci RNA RNA Splicing Regulation Regulator Genes Regulatory Element Research Resolution Resources Sample Size Sampling Science Specificity Structure Technology Time Tissue Sample Tissues Untranslated RNA Variant Work XCL1 gene biobank cell type computerized tools cost data integration data management data sharing epigenomics gene regulatory network genetic analysis genetic variant genome wide association study human disease human tissue innovation interest meetings model organism multiple omics operation postnatal postnatal development postnatal human preservation programs rare variant scaffold single cell technology single nucleus RNA-sequencing spatial relationship spatiotemporal trait transcriptome transcriptome sequencing transcriptomics

项目摘要

ABSTRACT Understanding the transcriptional programs governing cell identity and function is key to many outstanding questions in biology and biomedicine. Most variants associated with common diseases and traits lie in non- coding, regulatory regions of the genome, and to interpret their function, we need to identify the genes they affect and how those are expressed in the different cells of a tissue within individuals, and quantify how their expression varies across individuals. How these mechanisms are regulated during human development remains poorly understood, and most studies to date have relied on human cell lines or model organisms as proxies. GTEx did not profile tissues from postnatal stages of human development. Regulatory elements and gene networks are highly cell type–specific, and may only be active during precise developmental stages, during which they may also contribute to disease susceptibility. Thus, there is a critical need for measuring the transcriptional and regulatory landscape of tissues and cell types during human development. We will serve as the LDACC for the creation of the developmental GTEx (dGTEx) resource. (1) We will work with the BPC to establish a biobank of 30 tissues from each of 120 human postnatal postmortem donors, consented for broad research use and data sharing. (2) We will select 4 tissues of importance for common diseases, and in which there is tissue remodelling during development - brain, gut, lung and heart. We will profile these tissues with multiple single cell assays including snRNA-seq, multiomic RNA/ATAC, and spatial transcriptomics to create deep molecular maps for variant characterization. (3) We will perform baseline molecular profiling of genome sequence and bulk transcriptome for all samples, and integrate the resource with GTEx. We will use these collective data to identify e/sQTLs; create maps of element-gene relationships across tissues; chart differentiation hierarchies within tissues and across age ranges; nominate cell types in which a set of variants manifest; and map cellular and spatial relationships among cells, cellular programs, and tissue features. This project brings together a team with expertise in human genetics, production science (GTEx, ENCODE), computational biology, single cell technologies, and common disease genetics. We will create a data and biospecimen resource for the scientific community that will underpin studies to understand cellular and tissue changes during human development, genome regulation, and common disease variant interpretation.

抽象的了解控制细胞身份和功能的转录程序是许多杰出科学家的关键生物学和生物医学中的大多数与常见疾病和特征相关的变异都存在于非基因组的编码、调控区域，并解释它们的功能，我们需要识别它们影响的基因以及它们如何在个体组织的不同细胞中表达，并量化它们的表达如何这些机制在人类发育过程中的调节方式仍然很差。迄今为止，大多数研究都像 GTEx 一样依赖于人类细胞系或模型生物体。不分析人类发育出生后阶段的组织。高度细胞类型特异性，并且可能仅在精确的发育阶段活跃，在此期间它们可能也有助于疾病易感性，因此，迫切需要测量转录和水平。人类发育过程中组织和细胞类型的调控景观。 (1) 我们将作为 LDACC 创建开发性 GTEx (dGTEx) 资源。与 BPC 合作建立一个生物库，其中包含 120 名人类产后尸体捐献者的每人 30 个组织， (2)我们将选择4个重要的组织来进行常见的疾病，并且在发育过程中存在组织重塑——大脑、肠道、肺和心脏。对这些组织进行多种单细胞分析，包括 snRNA-seq、多组学 RNA/ATAC 和空间分析转录组学以创建用于变异表征的深层分子图谱 (3) 我们将执行基线。对所有样本的基因组序列和批量转录组进行分子分析，并将资源与我们将使用这些集体数据来识别 e/sQTL；创建元素-基因关系图谱；组织；绘制组织内和跨年龄范围的分化层次；指定一组细胞类型；变异的表现；并绘制细胞、细胞程序和组织之间的细胞和空间关系特征。该项目汇集了一支在人类遗传学、生产科学（GTEx、 ENCODE）、计算生物学、单细胞技术和常见疾病遗传学我们将创建数据。科学界的生物样本资源，将支持了解细胞和组织的研究人类发育、基因组调控和常见疾病变异解释过程中的变化。