Cellular and Molecular Mechanisms of Left Ventricular Growth and Morphogenesis
左心室生长和形态发生的细胞和分子机制
基本信息
- 批准号:8657292
- 负责人:
- 金额:$ 39万
- 依托单位:
- 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:2013-12-15 至 2017-11-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAllelesAnimal ModelAutomobile DrivingBHLH ProteinCardiacCardiac MyocytesCardiac OutputCell LineageCellsChildhoodClinicalCommon VentricleCongenital AbnormalityCongenital Heart DefectsCongenital atresia of pulmonary valveDevelopmentEmbryoEmbryonic DevelopmentEmbryonic HeartEnhancersEtiologyGene ExpressionGene TargetingGenesGeneticGerm-Line MutationGrowthGrowth and Development functionHeartHelix-Turn-Helix MotifsHumanHypoplastic Left Heart SyndromeInvestigationKnock-outLeftLeft ventricular structureLightLungModelingMolecularMorphogenesisMutationMyocardialMyocardiumNeural Crest CellOnline Mendelian Inheritance In ManOutcomePathway interactionsPatientsPhenotypePlayPopulationPositioning AttributePulmonary artery structureRegulatory ElementReportingRight ventricular structureRoleSeriesSideSomatic MutationTestingTranscription factor genesTransgenic OrganismsTricuspid AtresiaVenousVentricularVentricular septumcardiogenesiscongenital heart disordergain of function mutationhuman diseaseinsightloss of functionloss of function mutationmigrationmutantnoveloutcome forecastprogramspublic health relevancetranscription factor
项目摘要
PROJECT SUMMARY/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 and include
Tricuspid Atresia (OMIM# 605067), Pulmonary Atresia (OMIM# 265150), and Hypoplastic Left Heart Syndrome
(HLHS; OMIM# 241550, 614435). The single ventricle heart presents with a series circuit such that systemic
venous return to the right ventricle and pulmonary arteries combined with the flow from the pulmonary venous
return into the left ventricle and out to the body is incompatible with survival. Currently, there is a poor
understanding of the molecular mechanisms and cellular etiology causative of the many forms of single
ventricle CHD.
Human mutations in the cardiac transcription factor genes NKX2.5 and HAND1 have been observed in HLHS
patients. Modeling and thus the study of possible HLHS phenotypes have been limited as current systemic and
conditional knockouts of Nkx2.5 and Hand1 results in embryonic lethality given the broad expression domains
of available Cre lines. The lack of a restricted left ventricle Cre driver prohibits such investigations. Hand1 is
expressed within the primary heart field myocardium of the left ventricle. We have isolated the enhancer that
regulates Hand1 left ventricular expression and used it to generate a novel left ventricular-specific Cre driver
with which interrogation of the cellular and molecular mechanism driving left ventricular morphogenesis can be
realized. Our experimental plan is to ablate the Hand1 left ventricular lineage cells from the developing
embryonic heart, conditionally delete Nkx2.5 specifically within the left ventricular myocardium, and validate an
identified human mutation in HAND1 isolated from 24 unrelated patients as being causative of HLHS. This
study of the role that Hand1-lineage myocardium plays during cardiogenesis will shed light on the cell etiology
of single ventricle phenotypes and on the molecular programs controlling ventricular maturation, thus
expanding the understanding of ventricular morphogenesis as it relates to human disease.
Relevance:
CHDs resulting in single ventricle phenotypes have the poorest clinical outcomes. Thus, gaining an
understanding of the etiology and molecular mechanisms that cause CHDs resulting in a single ventricle heart
has the potential to benefit thousands of pediatric patients annually. The Hand1-lineage plays a key role in the
genesis of single ventricle phenotypes and gaining insight into the cellular and molecular mechanism of this
understudied myocardial population will have a great benefit to developing non-surgical treatments for CHD
patients.
项目总结/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
心室形态发生改变导致的表型具有最差的临床表现,包括
三尖瓣闭锁(OMIM# 605067)、肺动脉闭锁(OMIM# 265150)和左心发育不良综合征
(HLHS; OMIM# 241550,614435)。单心室心脏呈现串联回路,使得全身性
静脉回流到右心室和肺动脉,并与来自肺静脉的血流结合
回到左心室再回到身体是不可能存活的。目前,贫困
了解导致多种形式的单克隆抗体的分子机制和细胞病因学
心室CHD
在HLHS中观察到心脏转录因子基因NKX2.5和HAND 1的人类突变
患者建模和因此可能的HLHS表型的研究已被限制,因为当前的系统和
条件性敲除Nkx2.5和Hand 1导致胚胎致死,
可用的Cre线。由于缺乏受限制的左心室Cre驱动器,因此无法进行此类研究。手1
在左心室的主要心脏区域心肌内表达。我们分离出了一种增强剂
调节Hand 1左心室表达,并使用它来产生一种新的左心室特异性Cre驱动程序
通过这种方法,可以询问驱动左心室形态发生的细胞和分子机制,
实现了我们的实验计划是将Hand 1左心室谱系细胞从发育中的
胚胎心脏,特异性地在左心室心肌内有条件地删除Nkx2.5,并验证了
鉴定了从24名无关患者中分离的HAND 1中的人类突变是HLHS的病因。这
研究Hand 1系心肌在心脏发生过程中的作用将有助于阐明细胞病因学
单心室表型和控制心室成熟的分子程序,
扩大了对心室形态发生的理解,因为它与人类疾病有关。
相关性:
导致单心室表型的CHD具有最差的临床结局。因此,
了解导致单心室心脏的CHD的病因学和分子机制
每年有可能使成千上万的儿科患者受益。Hand 1-lineage在人类基因组中起着关键作用。
单心室表型的发生,并深入了解这种现象的细胞和分子机制,
研究不足的心肌人群将对开发冠心病的非手术治疗方法有很大好处
患者
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Anthony B. Firulli其他文献
Twist-family member interactions regulate cardiac neural crest morphogenesis
- DOI:
10.1016/j.ydbio.2009.05.227 - 发表时间:
2009-07-15 - 期刊:
- 影响因子:
- 作者:
Joshua W. Vincentz;Ralston M. Barnes;Beth A. Firulli;Simon J. Conway;Anthony B. Firulli - 通讯作者:
Anthony B. Firulli
<em>Twist1</em> is required for cardiac neural crest morphogenesis
- DOI:
10.1016/j.ydbio.2008.05.126 - 发表时间:
2008-07-15 - 期刊:
- 影响因子:
- 作者:
Joshua W. Vincentz;Ralston M. Barnes;Rhonda Rogers;Beth A. Firulli;Simon J. Conway;Anthony B. Firulli - 通讯作者:
Anthony B. Firulli
Maturation of human cardiac organoids enables complex disease modeling and drug discovery
人源心脏类器官的成熟使复杂疾病建模和药物发现成为可能
- DOI:
10.1038/s44161-025-00669-3 - 发表时间:
2025-06-25 - 期刊:
- 影响因子:10.800
- 作者:
Mark W. Pocock;Janice D. Reid;Harley R. Robinson;Natalie Charitakis;James R. Krycer;Simon R. Foster;Rebecca L. Fitzsimmons;Mary Lor;Lynn A. C. Devilée;Christopher A. P. Batho;Natasha Tuano;Sara E. Howden;Katerina Vlahos;Kevin I. Watt;Adam T. Piers;Kaitlyn Bibby;James W. McNamara;Rebecca Sutton;Valerii Iaprintsev;Jacob Mathew;Holly K. Voges;Patrick R. J. Fortuna;Sebastian Bass-Stringer;Celine Vivien;James Rae;Robert G. Parton;Anthony B. Firulli;Leszek Lisowski;Hannah Huckstep;Sean J. Humphrey;Sean Lal;Igor E. Konstantinov;Robert G. Weintraub;David A. Elliott;Mirana Ramialison;Enzo R. Porrello;Richard J. Mills;James E. Hudson - 通讯作者:
James E. Hudson
PDGFRA is a conserved HAND2 effector during early cardiac development
PDGFRA 是早期心脏发育过程中一个保守的 HAND2 效应因子。
- DOI:
10.1038/s44161-024-00574-1 - 发表时间:
2024-12-10 - 期刊:
- 影响因子:10.800
- 作者:
Yanli Xu;Rupal Gehlot;Samuel J. Capon;Marga Albu;Jonas Gretz;Joshua Bloomekatz;Kenny Mattonet;Dubravka Vucicevic;Sweta Talyan;Khrievono Kikhi;Stefan Günther;Mario Looso;Beth A. Firulli;Miloslav Sanda;Anthony B. Firulli;Scott Allen Lacadie;Deborah Yelon;Didier Y. R. Stainier - 通讯作者:
Didier Y. R. Stainier
Anthony B. Firulli的其他文献
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{{ truncateString('Anthony B. Firulli', 18)}}的其他基金
Transcriptional regulation of cardiac conduction system morphogenesis
心脏传导系统形态发生的转录调节
- 批准号:
10425653 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
Transcriptional regulation of cardiac conduction system morphogenesis
心脏传导系统形态发生的转录调节
- 批准号:
10428346 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
Transcriptional regulation of cardiac morphogenesis
心脏形态发生的转录调控
- 批准号:
10495950 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
Morphogenesis and growth of the ventricular wall in development and disease
发育和疾病中心室壁的形态发生和生长
- 批准号:
9208530 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
Morphogenesis and growth of the ventricular wall in development and disease
发育和疾病中心室壁的形态发生和生长
- 批准号:
10495945 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
Endocardial mechanisms of cardiac trabeculation and septation
心脏小梁形成和分隔的心内膜机制
- 批准号:
8901593 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
Endocardial mechanisms of cardiac trabeculation and septation
心脏小梁形成和分隔的心内膜机制
- 批准号:
8607702 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
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