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Early Cardiac Progenitors

早期心脏祖细胞

基本信息

批准号：
10579209
负责人：
Benoit Gaetan Bruneau
金额：
$ 56.49万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579209
关键词：
ATAC-seq Adult Affect Arrhythmia Behavior Birds Birth Cardiac Cardiomyopathies Cause of Death Cells Chromatin Complex Congenital Heart Defects DNA Defect Embryo Embryonic Development Embryonic Heart Enhancers Event Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Genetic study Genome Genomics Heart Heart Diseases Human Human Genetics Image Impairment In Vitro Individual Instruction Knock-out Knowledge Label Light Live Birth Mesoderm Modality Molecular Morphogenesis Mus Nature Organ Population Positioning Attribute Process Recipe Regulatory Element Reporter Genes Signal Transduction Specific qualifier value Testing Transgenic Organisms Tube Visualization Zebrafish cardiogenesis cell motility embryonic stem cell gastrulation gene regulatory network genome-wide heart cell in vivo induced pluripotent stem cell infant death marker transgenes microscopic imaging migration mutant precursor cell progenitor response single-cell RNA sequencing transcription factor transcriptome

项目摘要

SUMMARY The mammalian heart forms early in embryogenesis, and defects in its formation are at the root of congenital heart defects (CHDs), affecting 1–2% of live births. The gene regulatory networks that are disturbed in CHDs have begun to be elucidated from large-scale human genetic studies. Many of the genes causing CHD are transcriptional regulators, and several of these are also associated with genetics of adult heart disease, such as cardiomyopathy and arrhythmias. A complete understanding of the birth of cardiac progenitors and the first steps that lead to the formation of the embryonic heart has implications for both CHD and adult heart disease. The origins of the heart in embryogenesis have been defined as beginning in mesoderm that arises during gastrulation. We previously defined a specific enhancer of Smarcd3 that labels a very restricted subpopulation of Mesp1 lineage-labeled mesoderm, which contribute almost exclusively to the heart. Embryogenesis is a highly dynamic process, whereby complex coordinated cell movements position organ precursors for precise morphogenesis, and control the response to potent morphogenetic signaling gradients. While aspects of dynamic cardiac morphogenesis have been visualized in the avian embryo, our knowledge of cardiac progenitor emergence and behaviour in the mouse embryo is lacking. We have been able to culture and image live lineage- labeled mouse embryos, and will leverage this exciting approach to investigate mammalian cardiac development. We hypothesize that differentiation, migration, and contribution to early heart formation of early cardiac progenitors are regulated by a specific gene regulatory network composed of temporally-modulated DNA regulatory elements and the coordinated function of a cascade of transcriptional regulators. We will test this hypothesis in two Specific Aims. Specific Aim 1: To define genome-wide the gene regulatory networks that control the emergence of early cardiac progenitors. We will define genome-wide regulatory networks that control the specification, migration, and differentiation of early cardiac precursor using transgenic reporter lines combined with single cell RNA-seq and single cell ATACseq (for chromatin accessibility) in normal and mutant embryonic heart development Specific Aim 2. To visualize the birth and migration of early cardiac progenitors with live embryo imaging. In this aim, we will use live embryo light sheet microscopic imaging of lineage-labeled mouse embryos to visualize in 4D the live dynamic emergence of cardiac progenitors, their migration, and their collective behaviours during early cardiac morphogenesis. We will further image in live embryos in 4D early cardiac progenitors in the context of impaired migration (Mesp1 knockout embryos) and defective differentiation of first or second heart fields (Tbx5 and Mef2c knockout embryos). From transcription factor footprints in the genome, to transcriptomes, to live cells in vivo, our project will elucidate at the single cell level the molecular nature of the earliest cardiac precursors.

总结