PROJECT II: Vertebrate Animal Models of Cornelia de Lange Syndrome
PROJECT II: Vertebrate Animal Models of Cornelia de Lange Syndrome
批准号:
8378230
负责人:
Arthur D Lander
金额:
$50.67万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-02-01 至 2016-01-31
关键词:
AddressAllelesAnimal ModelAnimalsAtrial Heart Septal DefectsBackBehavioralBindingBody SizeBone GrowthBruck-de Lange syndromeCardiacCell LineChromosome CohesionCongenital AbnormalityCongenital Heart DefectsCraniofacial AbnormalitiesDNA SequenceDefectDevelopmentEmbryoEmbryonic DevelopmentEndocardiumEndodermEtiologyEventExhibitsFailure to ThriveFarGoFishesFrequenciesFunctional disorderGene ExpressionGene Expression ProfilingGene Expression RegulationGene TargetingGeneral PopulationGenesGeneticGoalsHealthHeartHeart Septal DefectsHumanIn SituIndividualInstructionIntronsLeftLinkMediatingMesodermModelingMolecularMorphogenesisMouse StrainsMusMutant Strains MiceMutationMyocardiumNatureNeural CrestObesityPathway interactionsPatternPhenocopyPhenotypePrincipal InvestigatorProbabilityProteinsResearchRoleSecondary toSeizuresSyndromeSystemTestingTimeTissuesTransgenic MiceUrsidae FamilyVentricular septumVertebratesWorkZebrafishbody systemcardiogenesiscell typecohesincombinatorialfunctional restorationgastrulationgene functionhuman diseaseinsightmigrationmutantnovelpreventprogenitorprotein complexrecombinaseresearch study
中文摘要
Cornelia de Lange综合征(CdLS)是一种由多器官系统星座引起的出生缺陷
英文摘要
Cornelia de Lange Syndrome (CdLS) is a multi-organ system constellation of birth defects caused by
dysfunction of cohesin, a protein complex required for chromosome cohesion, and recently implicated in
the regulation of gene expression. This work will continue the development and analysis of two animal
models of A//pib/-deficiency, the most common genetic cause of CdLS. The Nipbl+I- mouse replicates
many features of CdLS including a high frequency of cardiac septal abnormalities. The A//pW-morphant
zebrafish also displays cardiac defects, as well as gut defects that are typical of CdLS. In both systems,
Nipbl deficiency appears to cause hundreds of relatively small, often tissue-specific, changes in gene
expression, just as has been seen in cell lines from individuals with CdLS. The goal of the proposed work
is to exploit the mouse and fish models to (1) understand the origins of heart defects in CdLS, and (2)
determine the extent to which major structural defects in CdLS have a combinatorial etiology-i.e. arise
as the result of synergistic interactions among small changes in the expression of multiple genes. The
first aim will be accomplished using newly-developed transgenic mouse lines that harbor
conditional/invertible (FLEx) alleles of Nipbl, which may be successively toggled from functionally-mutant
to wildtype, and back again to mutant. Using these mouse lines, the timing and cell type(s) of origin of
cardiac septal defects will be pinpointed, and potentially causal changes in gene expression identified.
The second aim will be accomplished using a zebrafish model of CdLS. Experiments in this aim will focus
on the identification of new potential Nipbl "target" genes, and the quantitative manipulation of their
expression during early embryogenesis.
Accomplishing these aims should not only aid in understanding, treating and/or preventing birth defects in
CdLS; it is also likely to provide novel insights into the origins of non-syndromic birth defects, which are
much more common, but may also frequently result from combinatorial interactions among small-effect
alleles in the general population.
RELEVANCE (See instructions):
The impact of structural birth defects on human health is enormous. Animal models of Cornelia de Lange
Syndrome (CdLS) will be exploited to generate new insights into the origins of birth defects, especially
those of the heart and gut. Because of the way the gene defect underlying this syndrome works, there is
a good probability that the results obtained will be directly relevant to common causes of birth defects in
the general population.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mathematical, Computational and Systems Biology
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批准号:10642829
-
项目类别:
-
资助金额:$36.19万
-
财政年份:2020
-
负责人:Arthur D Lander
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依托单位:
Mentor Training to enhance mentorship in an interdisciplinary training program
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批准号:10393853
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项目类别:
-
资助金额:$8.64万
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财政年份:2020
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负责人:Arthur D Lander
-
依托单位:
Mathematical, Computational and Systems Biology
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批准号:10172935
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项目类别:
-
资助金额:$43.03万
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财政年份:2020
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负责人:Arthur D Lander
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依托单位:
Mathematical, Computational and Systems Biology
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批准号:10430156
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项目类别:
-
资助金额:$46.31万
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财政年份:2020
-
负责人:Arthur D Lander
-
依托单位:
Systems Biology Core
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批准号:10199940
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项目类别:
-
资助金额:$20.72万
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财政年份:2019
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负责人:Arthur D Lander
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依托单位:
Systems Biology Core
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批准号:10385798
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项目类别:
-
资助金额:$20.72万
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财政年份:2019
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负责人:Arthur D Lander
-
依托单位:
Systems Biology Core
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批准号:10618820
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项目类别:
-
资助金额:$20.72万
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财政年份:2019
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负责人:Arthur D Lander
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依托单位:
Outreach Core
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批准号:10392895
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项目类别:
-
资助金额:$16.75万
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财政年份:2018
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负责人:Arthur D Lander
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依托单位:
Complexity, Cooperation and Community in Cancer
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批准号:10392892
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项目类别:
-
资助金额:$187.91万
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财政年份:2018
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负责人:Arthur D Lander
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依托单位:
A National Short Course in Systems Biology: Tackling Spatial Dynamics in Cells an
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批准号:8079134
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项目类别:
-
资助金额:$18.36万
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财政年份:2011
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负责人:Arthur D Lander
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依托单位:
A National Short Course in Systems Biology: Tackling Spatial Dynamics in Cells an
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批准号:8310057
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项目类别:
-
资助金额:$17.92万
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财政年份:2011
-
负责人:Arthur D Lander
-
依托单位:
A National Short Course in Systems Biology: Tackling Spatial Dynamics in Cells an
-
批准号:8668078
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项目类别:
-
资助金额:$16.71万
-
财政年份:2011
-
负责人:Arthur D Lander
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依托单位:
THE MECHANISM OF DPP TRANSPORTATION
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批准号:8365759
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项目类别:
-
资助金额:$1.98万
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财政年份:2011
-
负责人:Arthur D Lander
-
依托单位:
A National Short Course in Systems Biology: Tackling Spatial Dynamics in Cells an
-
批准号:8854097
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项目类别:
-
资助金额:$16.47万
-
财政年份:2011
-
负责人:Arthur D Lander
-
依托单位:
A National Short Course in Systems Biology: Tackling Spatial Dynamics in Cells an
-
批准号:8474792
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项目类别:
-
资助金额:$16.35万
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财政年份:2011
-
负责人:Arthur D Lander
-
依托单位:
THE MECHANISM OF DPP TRANSPORTATION
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批准号:8170980
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项目类别:
-
资助金额:$1.66万
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财政年份:2010
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负责人:Arthur D Lander
-
依托单位:
Systems Biology of Morphogenesis and Spatial Information Flow
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批准号:8053161
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项目类别:
-
资助金额:$17.59万
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财政年份:2010
-
负责人:Arthur D Lander
-
依托单位:
COURSE ON CELL BIOLOGY & MICROSCOPY FOR THE INCOMING MCSB GRAD STUDENTS
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批准号:8170958
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项目类别:
-
资助金额:$0.18万
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财政年份:2010
-
负责人:Arthur D Lander
-
依托单位:
THE MECHANISM OF DPP TRANSPORTATION
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批准号:7956564
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项目类别:
-
资助金额:$5.85万
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财政年份:2009
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负责人:Arthur D Lander
-
依托单位:
Mathematical, Computational and Systems Biology
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批准号:7798986
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项目类别:
-
资助金额:$22.53万
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财政年份:2009
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负责人:Arthur D Lander
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依托单位:
海外基金