Transcriptional regulation of cardiac morphogenesis

心脏形态发生的转录调控

• 批准号: 9208535
• 负责人: Anthony B. Firulli
• 金额: $ 49.44万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208535
• 关键词: Address; Adolescent; Adult; Affect; Age; Area; Automobile Driving; BHLH Protein; Biological Process; Blood; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Cessation of life; Clinical; Code; Common Ventricle; Congenital Abnormality; Congenital Heart Defects; Defect; Development; Developmental Process; Diagnosis; Dimerization; Disease; Embryo; Enhancers; Etiology; Exhibits; Fibrosis; Frameshift Mutation; Gene Mutation; Gene Targeting; Genes; Genetic Enhancer Element; Genetic Transcription; Germ-Line Mutation; Goals; Growth; Health; Heart; Heart failure; Helix-Turn-Helix Motifs; Heritability; Human; Impairment; Inherited; Intraventricular; Lead; Left; Left ventricular structure; Mission; Modeling; Molecular; Morphogenesis; Morphology; Mus; Mutation; Myocardial; Myocardial dysfunction; Myocardium; National Heart, Lung, and Blood Institute; Nature; Nonsense Mutation; Outcome; Papillary; Patients; Pattern; Phenocopy; Phenotype; Placenta; Play; Prevention; Process; Proteins; Regulator Genes; Regulatory Element; Reporting; Research; Research Proposals; Series; Testing; Time; Tissues; Transcription Initiation Site; Transcriptional Regulation; United States National Institutes of Health; Untranslated RNA; Ventricular; Ventricular Septal Defects; Workload; body system; cardiogenesis; congenital heart disorder; dimer; experimental study; insight; loss of function; loss of function mutation; mutant; neonatal death; novel; offspring; papillary muscle; pediatric patients; postnatal; precursor cell; public health relevance

ABSTRACT Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses. CHDs that present with defective ventricular morphogenesis allow for the mixing of oxygenated and deoxygenated blood via ventricular septal defects (VSDs) and/or impaired contractile function both of which put limits on vitality. Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the many forms of ventricular CHDs. Hand1 is expressed within the developing left ventricle (LV) myocardium and the myocardial cuff (MC) between embryonic day (E) E8.5 and E13.5. Gene targeting models establish that Hand1 is required for normal LV development. We show that cardiomyocyte deletion of Hand1 results in surviving mice that present with CHDs effecting LV morphology. Recently, HAND1 mutations have been identified in patients diagnosed with CHDs. These HAND1 gene mutations manifest as frameshift or nonsense mutations within the protein coding domains and are reported to be somatic in nature, as germline mutations in HAND1 are assumed to be embryonic lethal. Like all genes, Hand1 is transcriptionally regulated through cis-element enhancers located within Conserved Non-coding Sequences (CNS) that are present both 5' and 3' to the Hand1 transcriptional start site. The notion that CNS gene mutations affecting the function of Hand1 through defects in cardiac transcriptional regulatory elements is a largely unexplored hypothesis that could provide a mechanism for heritable Hand1 cardiac loss-of-function in human CHDs. RELEVANCE CHDs resulting in ventricle phenotypes have the poorest clinical outcomes. Thus, gaining an understanding of the etiology and molecular mechanisms that cause CHDs resulting in altered ventricular morphogenesis has the potential to benefit thousands of pediatric patients annually. Hand1 plays a key role in cardiomyocyte patterning and gaining insight into the cellular and molecular mechanism of this understudied developmental process will have a great benefit to developing non-surgical treatments for CHD patients.

摘要 先天性心脏病（CHD）是最常见的出生缺陷。在各种CHD中，单心室 由心室形态发生改变引起的表型具有最差的临床表现。CHD， 存在心室形态发生缺陷，允许氧合血和脱氧血混合 通过室间隔缺损（VSD）和/或收缩功能受损，这两者都限制了生命力。 目前，对引起这些疾病的分子机制和细胞病因学的了解很少。 多种形式的心室CHD。 Hand 1在发育中的左心室（LV）心肌和心肌袖（MC）中表达。 在胚胎日（E）E8.5和E13.5之间。基因靶向模型建立了Hand 1是 正常的LV发育。我们发现，心肌细胞缺失Hand 1导致存活的小鼠， 冠心病影响左心室形态最近，HAND 1突变已经在诊断为 患有冠心病这些HAND 1基因突变表现为蛋白质内的移码或无义突变， 编码结构域，并报告为体细胞的性质，因为HAND 1中的种系突变被认为是 胚胎致死像所有的基因一样，Hand 1通过顺式元件增强子进行转录调控， 在保守的非编码序列（CNS）内，其存在于Hand 1转录的5'和3'端， 启动站点。CNS基因突变通过心脏缺陷影响Hand 1功能的观点 转录调节元件是一个基本上未经探索的假设，可以提供一种机制， 人类CHD中遗传性Hand 1心脏功能丧失。 相关性 导致心室表型的CHD具有最差的临床结局。因此，了解 导致CHD的病因学和分子机制导致心室形态发生改变， 每年有可能使数千名儿科患者受益。Hand 1在心肌细胞中起关键作用 模式化并深入了解这种未充分研究的发育的细胞和分子机制， 这一过程将对开发冠心病患者的非手术治疗方法大有益处。