Combinatorial Regulation of Gene Networks During Cardiac Development and Disease
心脏发育和疾病过程中基因网络的组合调控
基本信息
- 批准号:10245023
- 负责人:
- 金额:$ 273.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAdultAnatomyArchitectureBioinformaticsCRISPR/Cas technologyCardiacCardiac MyocytesCardiac developmentCardiovascular DiseasesCellsChromatinChromatin Remodeling FactorChromatin StructureCodeComplexCongenital AbnormalityCongenital Heart DefectsDNADNA BindingData SetDevelopmentDimerizationGATA4 geneGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGenomeGenome engineeringGenomicsHeart DiseasesHeart failureHumanInterventionKnowledgeLocationMorphogenesisMutateMutationNuclearNuclear Pore ComplexNuclear Pore Complex ProteinsOutputPaperPlayPost-Translational Protein ProcessingProcessProgram Research Project GrantsProteinsProteomicsPublishingReadingRegenerative MedicineRegulationRepressionRoleSignal TransductionSpecificitySystemTestingTranscription Factor 3Transcriptional Regulationcardiogenesiscausal variantchromatin remodelingcombinatorialcongenital heart disorderdisease-causing mutationgenome-widegenomic locushuman diseaseinduced pluripotent stem cellinterestmembermortalitymultidisciplinarymyocardinprotein protein interactionrecruitregenerative cellsynergismtranscription factor
项目摘要
PROJECT SUMMARY/ABSTRACT
OVERALL COMPONENT
Cardiovascular disease is the most common cause of mortality in adults, and congenital heart defects (CHDs)
are the most common form of birth defects. An important concept that has emerged in recent years is that
dysregulation of cardiac transcription factor (TF) networks and related chromatin remodeling machinery
contributes to CHDs and heart failure. Forced expression of the core members of the TF network is sufficient to
reprogram non-myocytes into cardiomyocyte-like cells for regenerative medicine purposes, suggesting a
combinatorial code for determining cell fate. As genome-wide roles for critical TFs are being discovered, a
conceptual understanding of their function in higher order DNA organization is emerging. Evidence that the
three-dimensional organization of DNA promotes activation or repression of genomic loci has raised the
question of how cooperative protein-protein interactions involving TF and chromatin remodeling complexes
participate in this process. We have integrated a multidisciplinary team of developmental cardiologists,
computational biologists, and systems biologists, with expertise in CRISPR/Cas9 genome engineering in
human iPS cells, to investigate how the genome is regulated by TFs and chromatin remodelers to control
cardiac gene expression and fate. The specific hypotheses that we test in this proposal, which involve a
combination of core cardiac TFs that interact with one another to coordinately regulate cardiac gene
expression, are as follows: 1) that the cardiac TFs GATA4 and TBX5 interact in a lineage-specific fashion with
the nuclear pore complex to regulate the 3D genomic architecture and subsequent transcriptional output; 2)
that specific BAF chromatin remodeling complexes form dynamically to coordinate regulation of distinct
aspects of cardiac morphogenesis and lineage decisions through interaction with cardiac TFs; and 3) that the
MEF2C-myocardin complex, which interacts with GATA4, TBX5 and BAF60c, recruits a transcriptional
complex influenced by upstream signaling and myocardin dimerization to regulate cardiac gene expression.
To address these questions, we have integrated unique expertise in the study of protein-protein interactions
and post-translational modifications through the Advanced Proteomics Core; the ability to analyze complex
datasets of PPIs, DNA-binding, and transcriptional output related to transcriptional regulators through the
Advanced Bioinformatics Core; and the ability to leverage state-of-the-art genome engineering approaches
through the Genome Engineering Core. The questions in this proposal will be studied in the context of human
disease-causing mutations to reveal underlying mechanisms and paradigms that control normal and abnormal
cardiogenesis. The integrated knowledge developed here will enable a clear reading of the transcriptional
“code” for cardiac cell fate determination and differentiation that may be leveraged for interventions in CHD and
for regenerative medicine.
项目总结/文摘
项目成果
期刊论文数量(0)
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DEEPAK SRIVASTAVA其他文献
DEEPAK SRIVASTAVA的其他文献
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{{ truncateString('DEEPAK SRIVASTAVA', 18)}}的其他基金
Small molecule therapeutic for calcific aortic valve disease
钙化性主动脉瓣疾病的小分子治疗
- 批准号:
10735711 - 财政年份:2023
- 资助金额:
$ 273.2万 - 项目类别:
Aortic Valve Disease: Mechanisms and Therapeutic Approaches
主动脉瓣疾病:机制和治疗方法
- 批准号:
10548842 - 财政年份:2020
- 资助金额:
$ 273.2万 - 项目类别:
Combinatorial Regulation of Gene Networks During Cardiac Development and Disease
心脏发育和疾病过程中基因网络的组合调控
- 批准号:
10471980 - 财政年份:2019
- 资助金额:
$ 273.2万 - 项目类别:
Project 1: Regulation of gene networks through cardiac transcription factor interaction with the nuclear membrane
项目1:通过心脏转录因子与核膜相互作用调节基因网络
- 批准号:
10245029 - 财政年份:2019
- 资助金额:
$ 273.2万 - 项目类别:
Combinatorial Regulation of Gene Networks During Cardiac Development and Disease
心脏发育和疾病过程中基因网络的组合调控
- 批准号:
10006031 - 财政年份:2019
- 资助金额:
$ 273.2万 - 项目类别:
Project 1: Regulation of gene networks through cardiac transcription factor interaction with the nuclear membrane
项目1:通过心脏转录因子与核膜相互作用调节基因网络
- 批准号:
10471988 - 财政年份:2019
- 资助金额:
$ 273.2万 - 项目类别:
Project 1: Regulation of gene networks through cardiac transcription factor interaction with the nuclear membrane
项目1:通过心脏转录因子与核膜相互作用调节基因网络
- 批准号:
10006188 - 财政年份:2019
- 资助金额:
$ 273.2万 - 项目类别:
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