Transcriptional regulation of arteriovenous differentiation
动静脉分化的转录调控
基本信息
- 批准号:9376461
- 负责人:
- 金额:$ 52.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAllelesArteriesArteriovenous malformationAtherosclerosisBindingBioinformaticsBiological AssayBloodBlood VesselsBlood flowCalcifiedCardiovascular systemCell LineCellsCerebral Arteriovenous MalformationsChildhoodChildhood strokeChromatinCodeDataData SetDatabasesDiseaseEP300 geneEmbryoEndothelial CellsEnhancersFamilyGene ExpressionGenesGeneticGenetic TranscriptionGenetically Engineered MouseGenomicsGoalsHumanInflammationInformaticsKnowledgeLinkLocationMaintenanceMalignant NeoplasmsMapsMeasuresMediator of activation proteinMethodsMolecularMolecular ProfilingMusMutagenesisMyocardial IschemiaNatureNuclear ReceptorsOrphanPathogenesisPathway interactionsPluripotent Stem CellsPredispositionProcessRegulationRegulatory ElementSignal TransductionSpecific qualifier valueSpecificityStrokeStructureTechniquesTestingTissuesTranscriptional RegulationTransgenic OrganismsVEGFA geneValidationVasculitisVeinsVenousangiogenesisapoAI regulatory protein-1biochipcalcificationchicken ovalbumin upstream promoter-transcription factorembryo cellexperimental studygamma secretasegenome-widehigh throughput screeninghuman diseaseimprovedin vivoinduced pluripotent stem cellinhibitor/antagonistinnovationinsightmalformationmouse modelnotch proteinnovelnovel strategiespediatric patientsprecise genome editingprogramstranscription factor
项目摘要
Project Summary/Abstract
Endothelial cells (ECs) that line the blood circulatory system belong to the arterial and venous lineages. Ar-
terial and venous ECs intrinsically differ in their susceptibility to inflammation, atherosclerosis, and calcification.
Moreover, disruption of genetic programs that maintain AV differences in mouse models causes arteriovenous
malformations (AVMs), the leading cause of pediatric strokes. Thus understanding the genetic mechanisms
that specify and maintain AV differences is critical to better understand the pathogenesis of a range of human
disorders. Specification of arterial and venous lineages occurs prior to the establishment of blood flow, sug-
gesting that AV differences are primarily under genetic control. Despite extensive efforts, our understanding of
the molecular mechanisms that establish and maintain arterial and venous identity remains incomplete. Notch
signaling has been identified as being critical for arterial differentiation, and the transcription factor COUP-TFII
has been identified as being critical for venous differentiation, at least in part by antagonizing Notch signaling.
In depth study of 4 transcriptional enhancers with artery selective activity has yielded anecdotal information on
some features required for their artery-selective activity. However, systematic knowledge of principles that de-
termine arterial or venous specific expression is lacking. In large part, this is due to the low throughput nature
of the techniques that have been employed to study this problem.
We have developed two unique, high throughput approaches that will surmount this barrier and yield syste-
matic information about the mechanisms that are employed to yield artery or vein selective activity. First, we
developed a method for high affinity, tissue-specific identification of active enhancers marked by p300, and of
regulatory elements bound by the Notch target RBPJ. Second, we have developed a method for high through-
put (on the order of hundreds of thousands in one experiment) testing of candidate enhancers within an inte-
grated genomic context. In this proposal we apply these advances to systematically investigate arteriovenous
differentiation and the mechanisms by which it is regulated by Notch signaling.
In Aim 1, we test the hypothesis that identifiable transcriptional codes drive artery and vein specific
transcriptional enhancer activity. We will use p300 binding in ECs to identify candidate enhancers, and then
test the enhancers in parallel for artery or vein selective activity. Bioinformatic analyses of this database of
enhancers with selective activity will identify the candidate transcriptional lexicon. These predictions will be
tested by followup dense mutagenesis of selected enhancers, with further validation in transgenic embryo
assays.
In Aim 2, we focus on the mechanisms by which Notch signaling modulates RBPJ activity. We test the hy-
pothesis that RBPJ regulates AV differentiation through multiple distinct Notch-dependent and -independent
mechanisms. This aim hinges upon our unique ability to efficiently map RPBJ chromatin occupancy in vivo in
ECs. By mapping RBPJ and p300 under Notch activated and Notch suppressed conditions in developing em-
bryos, we will define the effects of Notch intracellular domain on RBPJ location and activity. Combining these
data with the artery and vein selective enhancers found in Aim 1 will define artery or vein selective enhancers
with Notch/RBPJ-dependent and -independent activity.
This proposal is technically innovative in the novel genome-wide mapping and high throughput enhancer
testing approaches. The conceptual innovation is the new understanding of artery or vein selective transcrip-
tional regulation and of Notch signaling that will arise from application of these novel approaches.
This proposal is significant because it will advance our understanding of angiogenesis by filling in critical
gaps in our understanding of how arteriovenous differences are specified and maintained. This basic knowl-
edge is relevant to diverse classes of human disease such as cancer, atherosclerosis, and inflammation.
项目总结/文摘
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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William Tswenching Pu的其他文献
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CMYA5 regulation of cardiac dyad structure and function
CMYA5对心脏二元体结构和功能的调节
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10607816 - 财政年份:2022
- 资助金额:
$ 52.34万 - 项目类别:
Genetic regulation of atrial gene expression in development and disease
发育和疾病中心房基因表达的遗传调控
- 批准号:
10576399 - 财政年份:2021
- 资助金额:
$ 52.34万 - 项目类别:
Genetic regulation of atrial gene expression in development and disease
发育和疾病中心房基因表达的遗传调控
- 批准号:
10355481 - 财政年份:2021
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Enabling mammalian in vivo forward genetic screens based on cell morphology
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- 批准号:
9754850 - 财政年份:2018
- 资助金额:
$ 52.34万 - 项目类别:
Transcriptional regulation of arteriovenous differentiation
动静脉分化的转录调控
- 批准号:
9751955 - 财政年份:2017
- 资助金额:
$ 52.34万 - 项目类别:
2015 Weinstein Cardiovaascular Development Conference
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- 资助金额:
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YAP1 Regulation of cardiomyocyte proliferation, function, and regeneration
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- 批准号:
8412652 - 财政年份:2013
- 资助金额:
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