Optogenetic regulation of intra-ciliary calcium signaling in cardiac situs development
心脏位置发育中纤毛内钙信号传导的光遗传学调控
基本信息
- 批准号:10640983
- 负责人:
- 金额:$ 55.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AbdomenAddressAffectBindingBinding SitesBiological AssayBiologyBody PatterningCalciumCalcium ChannelCalcium OscillationsCalcium SignalingCalcium-Binding ProteinsCalmodulinCalmodulin-Binding ProteinsCardiacCardiovascular systemCationsCell physiologyCellsChestCiliaComplexCongenital AbnormalityCongenital Heart DefectsCuesCytoplasmDataData AnalysesDefectDevelopmentDiagnosticDiseaseEmbryoEmbryologyEmbryonic DevelopmentEmbryonic FluidEukaryotic CellExtracellular FluidGap JunctionsGene ExpressionGeneticHandednessHeartHumanImageIonsKnowledgeLeftLightLive BirthLiverLungMachine LearningMediatingMicroscopyMicrotubulesModelingMolecularMorphogenesisMutationMyocardialNatural regenerationNodalOrganOrganellesPKD2 proteinPatient-Focused OutcomesPatternPerceptionPhenotypePlayPositioning AttributeProcessProteinsRegulationReporterResearchRoleSignal TransductionSitus InversusStructureSyndromeTechniquesTestingTherapeuticTransducersTranslatingVascular DiseasesWNT Signaling PathwayWorkZebrafishbasecalcium indicatorcardiogenesisciliopathycilium motilitycongenital heart disorderfluid flowimproved outcomein vivoin vivo calcium imaginginnovationmutantnoveloptogeneticsreceptorspatiotemporaltooltransmission process
项目摘要
PROJECT SUMMARY / ABSTRACT
Cilia, microtubule-based organelles found on nearly all eukaryotic cells, coordinate numerous signaling cascade
that are essential for vertebrate development and disease. Mutations in primary cilia are associated with
numerous cardiovascular defects, most notably major congenital heart diseases (CHD). Further, ciliary defects
are known to cause heterotaxy, a human disorder of abnormal left-right (LR) asymmetric body patterning that
commonly affects the heart and is tightly correlated with CHD. During embryogenesis, proper LR asymmetric
development requires motile cilia that move in a coordinated fashion to generate the initial signal to break LR
symmetry: leftward flow of extra-embryonic fluid in a structure called the “left-right organizer” (LRO). Although
leftward flow in the LRO is necessary and sufficient for LR development, how this flow is sensed and transduced
into phenotypic LR asymmetry remains unclear. Strikingly, we have generated preliminary data in the zebrafish
LRO that suggests immotile cilia may function as calcium-signaling compartments that coordinate downstream
Nodal signaling via gap junctions during LR development. To elucidate this potential mechanism, we propose
three scientific aims that combine state-of-the-art in vivo microscopy, optogenetic tools, machine learning data
analysis approaches, zebrafish genetics and molecular embryology. In Aim 1, we will combine light-sheet
microscopy and optogenetic actuators to regulate calcium dynamics in the LRO of zebrafish. Combined with new
quantitative machine learning analysis tools, this approach will enable us to definitively address whether intra-
ciliary calcium signaling is sufficient and instructive for LR development. In Aim 2, we will investigate the
molecular machinery that underlies cilia-mediated calcium signaling in LR development. Specifically, we will
examine how the Pkd1l1-Pkd2 polycystin complex interact with one another to mediate calcium signaling in the
zebrafish LRO. In Aim 3, we will investigate how cilia-mediated calcium signaling is transduced from the cilium
to the cytoplasm by Invs, a calcium binding protein which localizes to the base of LRO cilia and is required for
LR development. Completion of these studies will resolve the role of the cilium as mechanosensitive antennae
that sense and translate extra-embryonic fluid flow into calcium signals that build the LR axis and lead to a
greater understanding of the mechanisms that drive situs of the heart.
项目摘要/摘要
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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Shiaulou Yuan其他文献
Shiaulou Yuan的其他文献
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{{ truncateString('Shiaulou Yuan', 18)}}的其他基金
Optogenetic regulation of intra-ciliary calcium signaling in cardiac situs development
心脏位置发育中纤毛内钙信号传导的光遗传学调控
- 批准号:
10504671 - 财政年份:2022
- 资助金额:
$ 55.51万 - 项目类别:
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