Elucidating CHD in Down Syndrome with Cardiac Organoids and 3D Genome Architecture

利用心脏类器官和 3D 基因组架构阐明唐氏综合症中的 CHD

基本信息

批准号：
10852469
负责人：
Lei Stanley Qi
金额：
$ 38.58万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10852469
关键词：
3-Dimensional ATAC-seq Address Administrative Supplement Affect Architecture Bioinformatics Biometry Blood Vessels CRISPR interference Cardiac Cardiac Myocytes Cardiovascular system Cells Characteristics Chromatin Chromosome abnormality Collaborations Congenital Heart Defects Defect Development Developmental Biology Dilated Cardiomyopathy Diploidy Down Syndrome Elements Endothelial Cells Fibroblasts Gene Expression Gene Expression Regulation Genetic Transcription Genome Genomics Grant Heart Heart Diseases Hematology Human Individual Infant Methods Modeling Molecular Morbidity - disease rate Mutation Organoids Outcomes Research Parents Pathogenesis Pathway interactions Patients Phenotype Process Protocols documentation Role Sampling Signal Transduction Structure Technology Untranslated RNA Vascularization Wing biobank cardiac tissue engineering cardiogenesis cell type chromosome conformation capture congenital heart disorder disease-causing mutation epigenomics experience human disease in vitro Model induced pluripotent stem cell infant morbidity infant morbidity/mortality insight mortality multidisciplinary multiple omics novel therapeutic intervention response single-cell RNA sequencing

项目摘要

PROJECT SUMMARY Down syndrome (DS) or Trisomy 21 (T21) is a prevalent chromosomal defect worldwide, often associated with multiple cardiovascular and hematological anomalies. Congenital heart disease (CHD), affecting up to 50% of DS patients, is a leading cause of morbidity and mortality in infants. CHD is primarily caused by dysregulated transcriptional pathways. Although the 3D spatial organization of the genome has emerged as a crucial mechanism for regulating chromatin accessibility, its role in cell-to-cell variability and gene regulation within CHD remains poorly understood. In Aim 1, we will utilize 3D-vascularized cardiac organoids (3D-vCOs) and multi- omics approaches to elucidate the mechanisms of DS-associated cardiovascular complications. We will employ single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) to analyze the vascular network and cardiomyocyte (CM) characteristics, thereby establishing phenotypes of DS-CHDs. Our study will specifically focus on analyzing the vascular network and cardiomyocyte (CM) characteristics to establish phenotypes of Down syndrome-associated congenital heart defects (DS-CHDs). In Aim 2, we will perform Dip-C (Diploid Chromosome Conformation Capture) at specific timepoints during 3D-vCO culture (Day 3, Day 6, and Day 16) using DS patients iPSC lines. We will analyze the inter-chromosomal interactions (ICIs) and 3D architecture of the genome in 3D-vCOs, namely focusing on differences among the CMs, CFs, and ECs between DS-CHD versus DS-nonCHD patients. We anticipate gaining new mechanistic insights into the pathogenesis of DS-CHDs and facilitating the development of novel therapeutic strategies aimed at mitigating and reversing cellular abnormalities in the diseased heart.

项目摘要唐氏综合症（DS）或三体疾病21（T21）是全球普遍的染色体缺陷，通常与多个心血管和血液学异常。先天性心脏病（CHD），影响多达50％ DS患者是婴儿发病率和死亡率的主要原因。 CHD主要由失调引起转录途径。尽管基因组的3D空间组织已成为至关重要的调节染色质可及性的机制，其在细胞到细胞变异性中的作用和CHD内基因调节的作用仍然很了解。在AIM 1中，我们将利用3D血管性心脏器官（3D-VCO）和多 OMICS阐明与DS相关心血管并发症机制的方法。我们将雇用单细胞RNA测序（SCRNA-SEQ）和单细胞ATAC测序（SCATAC-SEQ），以分析血管网络和心肌细胞（CM）特征，从而建立了DS-CHD的表型。我们的研究将特别着重于分析血管网络和心肌细胞（CM）特征建立唐氏综合症相关的先天性心脏缺陷（DS-CHD）的表型。在AIM 2中，我们将在3D-VCO培养期间（天 3，第6天和第16天）使用DS患者IPSC系列。我们将分析染色体间相互作用（ICI） 3D VCO中基因组的3D结构，即关注CMS，CFS和EC之间的差异在DS-CHD与DS-NONCHD患者之间。我们预计将获得新的机械见解 DS-CHD的发病机理，并促进旨在缓解的新型治疗策略的发展并逆转患病心脏的细胞异常。