Transcriptional regulation of cardiac morphogenesis
Transcriptional regulation of cardiac morphogenesis
批准号:
9208535
负责人:
Anthony B. Firulli
金额:
$49.44万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-02-15 至 2022-01-31
关键词:
AddressAdolescentAdultAffectAgeAreaAutomobile DrivingBHLH ProteinBiological ProcessBloodCardiacCardiac MyocytesCardiomyopathiesCellsCessation of lifeClinicalCodeCommon VentricleCongenital AbnormalityCongenital Heart DefectsDefectDevelopmentDevelopmental ProcessDiagnosisDimerizationDiseaseEmbryoEnhancersEtiologyExhibitsFibrosisFrameshift MutationGene MutationGene TargetingGenesGenetic Enhancer ElementGenetic TranscriptionGerm-Line MutationGoalsGrowthHealthHeartHeart failureHelix-Turn-Helix MotifsHeritabilityHumanImpairmentInheritedIntraventricularLeadLeftLeft ventricular structureMissionModelingMolecularMorphogenesisMorphologyMusMutationMyocardialMyocardial dysfunctionMyocardiumNational Heart, Lung, and Blood InstituteNatureNonsense MutationOutcomePapillaryPatientsPatternPhenocopyPhenotypePlacentaPlayPreventionProcessProteinsRegulator GenesRegulatory ElementReportingResearchResearch ProposalsSeriesTestingTimeTissuesTranscription Initiation SiteTranscriptional RegulationUnited States National Institutes of HealthUntranslated RNAVentricularVentricular Septal DefectsWorkloadbody systemcardiogenesiscongenital heart disorderdimerexperimental studyinsightloss of functionloss of function mutationmutantneonatal deathnoveloffspringpapillary musclepediatric patientspostnatalprecursor cellpublic health relevance
中文摘要
摘要
英文摘要
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.
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会议论文
Transcriptional regulation of cardiac conduction system morphogenesis
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批准号:10425653
-
项目类别:
-
资助金额:$1.66万
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财政年份:2019
-
负责人:Anthony B. Firulli
-
依托单位:
Transcriptional regulation of cardiac conduction system morphogenesis
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批准号:10428346
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项目类别:
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资助金额:$67.15万
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财政年份:2019
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负责人:Anthony B. Firulli
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依托单位:
Administrative Core A
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批准号:9208531
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项目类别:
-
资助金额:$18.26万
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财政年份:2017
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负责人:Anthony B. Firulli
-
依托单位:
Transcriptional regulation of cardiac morphogenesis
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批准号:10495950
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项目类别:
-
资助金额:$53.24万
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财政年份:2017
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负责人:Anthony B. Firulli
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依托单位:
Morphogenesis and growth of the ventricular wall in development and disease
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批准号:10495945
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项目类别:
-
资助金额:$279.75万
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财政年份:2017
-
负责人:Anthony B. Firulli
-
依托单位:
Morphogenesis and growth of the ventricular wall in development and disease
-
批准号:9208530
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项目类别:
-
资助金额:$236.59万
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财政年份:2017
-
负责人:Anthony B. Firulli
-
依托单位:
Administrative Core
-
批准号:10495946
-
项目类别:
-
资助金额:$16.56万
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财政年份:2017
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负责人:Anthony B. Firulli
-
依托单位:
Endocardial mechanisms of cardiac trabeculation and septation
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批准号:8901593
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项目类别:
-
资助金额:$3.02万
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财政年份:2013
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负责人:Anthony B. Firulli
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依托单位:
Cellular and Molecular Mechanisms of Left Ventricular Growth and Morphogenesis
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批准号:8657292
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项目类别:
-
资助金额:$39.0万
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财政年份:2013
-
负责人:Anthony B. Firulli
-
依托单位:
Endocardial mechanisms of cardiac trabeculation and septation
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批准号:8607702
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项目类别:
-
资助金额:$39.0万
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财政年份:2013
-
负责人:Anthony B. Firulli
-
依托单位:
Cellular and Molecular Mechanisms of Left Ventricular Growth and Morphogenesis
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批准号:8786104
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项目类别:
-
资助金额:$38.42万
-
财政年份:2013
-
负责人:Anthony B. Firulli
-
依托单位:
Cellular and Molecular Mechanisms of Left Ventricular Growth and Morphogenesis
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批准号:8962164
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项目类别:
-
资助金额:$39.0万
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财政年份:2013
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负责人:Anthony B. Firulli
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依托单位:
The role of Twist family bHLH factors in limb morphogenesis
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批准号:8291150
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项目类别:
-
资助金额:$34.65万
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财政年份:2011
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负责人:Anthony B. Firulli
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依托单位:
The role of Twist family bHLH factors in limb morphogenesis
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批准号:8681363
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项目类别:
-
资助金额:$33.96万
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财政年份:2011
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负责人:Anthony B. Firulli
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依托单位:
The role of Twist family bHLH factors in limb morphogenesis
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批准号:8862389
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项目类别:
-
资助金额:$34.65万
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财政年份:2011
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负责人:Anthony B. Firulli
-
依托单位:
The role of Twist family bHLH factors in limb morphogenesis
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批准号:8160340
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项目类别:
-
资助金额:$34.65万
-
财政年份:2011
-
负责人:Anthony B. Firulli
-
依托单位:
The role of Twist family bHLH factors in limb morphogenesis
-
批准号:8479210
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项目类别:
-
资助金额:$32.92万
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财政年份:2011
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负责人:Anthony B. Firulli
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依托单位:
REGULATION OF CARDIAC MORPHOGENESIS
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批准号:7901821
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项目类别:
-
资助金额:$35.85万
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财政年份:2009
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负责人:Anthony B. Firulli
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依托单位:
REGULATION OF CARDIAC MORPHOGENESIS
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批准号:7264755
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项目类别:
-
资助金额:$12.0万
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财政年份:2007
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负责人:Anthony B. Firulli
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依托单位:
Transcription Factors Involved in Heart Development
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批准号:6795133
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项目类别:
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资助金额:$30.1万
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财政年份:1999
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负责人:Anthony B. Firulli
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依托单位:
海外基金