Reconstruction of cardiovascular regulatory networks from large-scale single-cell analyses of cardiovascular lineages

从心血管谱系的大规模单细胞分析重建心血管调节网络

• 批准号: 8996084
• 负责人: Neil C Chi
• 金额: $ 62.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996084
• 关键词: Accounting; Adult; Algorithms; Animal Model; Behavior; Biological Assay; Cardiovascular system; Cell Differentiation process; Cell Lineage; Cells; Chromatin; Collaborations; Communities; Computer Analysis; Data Set; Derivation procedure; Development; Developmental Gene; Event; Family; Fluorescent in Situ Hybridization; Future; Genes; Genetic study; Goals; Health; Heart; Heterogeneity; Histocompatibility Testing; Human; In Situ; In Vitro; Maintenance; Maps; Mediating; Modeling; Molecular; Molecular Genetics; Mutation; Network-based; Newborn Infant; Pathway interactions; Patients; Phenotype; Physicians; Pluripotent Stem Cells; Population; Population Heterogeneity; Principal Component Analysis; Process; Protein Isoforms; Regulator Genes; Regulatory Pathway; Reporter; Research; Signal Pathway; Societies; Specific qualifier value; Staging; Stem cells; Technology; Testing; Validation; base; cardiogenesis; cell type; cellular engineering; congenital anomaly; congenital heart disorder; differential expression; genetic information; improved; in vivo; innovation; insight; novel; patient population; progenitor; programs; reconstruction; single cell analysis; transcriptome; transcriptome sequencing; translational study

 DESCRIPTION (provided by applicant): The gene regulatory networks underlying early human cardiovascular (CV) development is poorly understood, in large part due to the dearth of molecular and genetic information specifying the diversity of cardiovascular progenitor cell-types (CVPCs). Human pluripotent stem cell (hPSC)-derived CV cells provide a model for human cardiogenesis and afford us the opportunity to reveal the various CV cell types generated during heart development and to also functionally discover and validate CV developmental gene regulatory networks. In this proposal, we will employ single cell transcriptome (RNA-seq) analysis to dissect the heterogeneity of early CV progenitor populations that give rise to the spectrum of distinct CV cell types and their intermediates. By identifying these potentially rare and novel progenitor cell types as well as studying their lineage choice decisions at the single cell level, the cellular and molecular networks underlying these progenitor cells and their differentiated CV cell types that control their differentiation can be revealed. To achieve our goal, a synergistic and complementary collaboration between the Yeo and Chi labs will aim to (1) investigate the diversity and organization of CV cellular subtypes during cardiogenesis in vitro, (2) develop novel algorithms that enable the extraction of gene regulatory programs that specify CV lineage sub-networks and (3) investigate the functional significance of identified CV cell subtypes. If successful, we will reveal pathways and cell-types that will advance our basic and translational framework for treating congenital heart disease.

 描述（由申请人提供）：人类早期心血管（CV）发育的基因调控网络知之甚少，很大程度上是由于缺乏指定心血管祖细胞类型（CVPC）多样性的分子和遗传信息。人类多能干细胞 (hPSC) 衍生的 CV 细胞为人类心脏发生提供了模型，使我们有机会揭示心脏发育过程中产生的各种 CV 细胞类型，并在功能上发现和验证 CV 发育基因调控网络。在本提案中，我们将采用单细胞转录组 (RNA-seq) 分析来剖析早期 CV 祖细胞群的异质性，这些祖细胞群产生了不同 CV 细胞类型及其中间体的谱系。通过鉴定这些潜在的稀有和新颖的祖细胞类型以及在单细胞水平上研究它们的谱系选择决策，可以揭示这些祖细胞及其控制其分化的分化的CV细胞类型背后的细胞和分子网络。为了实现我们的目标，Yeo 和 Chi 实验室之间的协同和互补合作将旨在 (1) 研究体外心脏发生过程中 CV 细胞亚型的多样性和组织，(2) 开发新的算法，能够提取指定 CV 谱系子网络的基因调控程序，以及 (3) 研究已识别的 CV 细胞亚型的功能意义。如果成功，我们将揭示途径和细胞类型，从而推进我们治疗先天性心脏病的基本和转化框架。