Control of epithelial morphology and bioenergetics by Toll receptors during dynamic tissue remodeling
动态组织重塑过程中 Toll 受体对上皮形态和生物能的控制
基本信息
- 批准号:10737093
- 负责人:
- 金额:$ 31.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:ActomyosinAddressAdhesionsAffectAnimalsAntibodiesArchitectureAreaAtlasesAttentionBioenergeticsBiomechanicsCRISPR/Cas technologyCell Adhesion InhibitionCell PolarityCell ShapeCell membraneCell-Cell AdhesionCellsCellular Metabolic ProcessCellular MorphologyChronicClustered Regularly Interspaced Short Palindromic RepeatsComplexCongenital AbnormalityCytoskeletonDataDefectDevelopmentDevelopmental BiologyDiseaseDrosophila genusEmbryoEmbryonic DevelopmentEmbryonic StructuresEngineeringEpithelial CellsEpitheliumFamilyFluorescenceG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGPCR Signaling PathwayGeneticGenetic TechniquesGenome engineeringGenomicsHealthHomeostasisHumanHuman PathologyImmune signalingImpaired wound healingIndividualInflammationIntercalated CellLabelLightLinkMalignant NeoplasmsMeasuresMediatorMetabolicMetabolismMicroscopyMitochondriaModelingMolecularMorphologyMultiphoton Fluorescence MicroscopyMutationMyosin ATPaseNADHNatureNeoplasm MetastasisNeuroectodermOxidation-ReductionPathway interactionsPatternPlayPositioning AttributeProcessProductionProteinsReceptor ActivationReceptor GeneReceptor SignalingRegulationRho-associated kinaseRoleShapesSignal PathwaySignal TransductionStereotypingStructureStudy modelsSystemTechniquesTertiary Protein StructureTestingTissuesToll-like receptorsTransgenic OrganismsVisualizationcell behaviorcofactorconvergent extensionepithelial woundexperimental studyfluorescence lifetime imagingfunctional lossgain of functionin vivointercalationloss of functionmembermodel organismmultiphoton microscopyreceptorreceptor expressionreceptor functionrhosealtumorwound healing
项目摘要
Project Summary
During development, epithelial cells undergo programmed changes in morphology and position to create
complex tissues. Studies in model organisms have identified a conserved set of effector proteins that directly
alter cell shape, although the upstream pathways that coordinate these processes across large groups of cells
remain poorly understood. A paradigm for studying epithelial remodeling is cell intercalation in the Drosophila
neurectoderm, and it was shown that three members of the highly conserved Toll receptor family are expressed
in overlapping striped patterns to organize rapid cell rearrangements in this tissue. Toll receptors are widely
expressed throughout human epithelia, and they have been extensively studied in the context of innate immune
signaling. However, the control of cell morphology by Toll receptors has received very little attention. The focus
of this proposal is to understand how non-uniform Toll receptor expression affects cortical tension, cell-cell
adhesion, and mitochondrial dynamics to control cell shape and behavior during epithelial remodeling. We will
use newly developed CRISPR/Cas9-derived genetic backgrounds and antibodies to characterize how Toll
receptors control cell polarity to trigger intercalation; we will apply non-destructive techniques to characterize the
bioenergetics of epithelial reorganization in intact living embryos; and we will investigate unaddressed links
between Toll receptor, Rho, and G protein-coupled receptor signaling. Our first hypothesis is that neighboring
cells sense differences in the expression of individual Toll receptor types to increase cortical tension and
decrease cell-cell adhesion. We have developed a genetic system for expressing individual receptors in a single
stripe that we will use to systematically characterize and compare the effects of each Toll receptor type on cell
morphology and to identify the protein domains necessary for modulating cell shape. Our second hypothesis is
that rapid cellular rearrangements during neurectoderm elongation require changes in mitochondrial signaling to
drive cytoskeletal and junctional reorganization. To test this, we will use multiphoton microscopy to visualize the
endogenous autofluorescence of metabolic cofactors to quantify cellular redox state in live embryos during
epithelial remodeling, and then use gain- and loss-of-function techniques to determine what role mitochondrial
fusion and fission play in epithelial reorganization. Our third hypothesis is that Toll receptor and GPCR signaling
converge to activate Rho Kinase and trigger cell intercalation in the neurectoderm. We will use gain- and loss-
of-functional analyses to determine how these two signaling pathways intersect to control cortical tension, cell-
cell adhesion, and mitochondrial dynamics during epithelial remodeling. Successful completion of these
experiments will give us a more comprehensive understanding of how Toll receptors function at a molecular level
to control cellular biomechanics and bioenergetics during dynamic tissue remodeling.
项目摘要
在发育过程中,上皮细胞经历形态和位置的程序性变化,
复杂的组织对模式生物的研究已经确定了一组保守的效应蛋白,它们直接
改变细胞的形状,虽然上游的途径,协调这些过程在大群细胞
仍然知之甚少。研究上皮重塑的一个范例是果蝇的细胞嵌入
神经外胚层,并且显示高度保守的Toll受体家族的三个成员表达
以重叠的条纹图案来组织中的快速细胞重排。Toll受体广泛存在于
在整个人类上皮细胞中表达,并且它们在先天免疫的背景下被广泛研究。
信号然而,Toll受体对细胞形态的控制很少受到关注。重点
这项建议的目的是了解Toll受体的非均匀表达如何影响皮质张力,细胞-细胞
粘附和线粒体动力学来控制上皮重塑期间的细胞形状和行为。我们将
使用新开发的CRISPR/Cas9衍生的遗传背景和抗体来表征Toll
受体控制细胞极性触发嵌入;我们将应用非破坏性技术来表征
在完整的活胚胎上皮重组的生物能量学;我们将调查未解决的联系
Toll受体、Rho和G蛋白偶联受体信号传导之间的关系。我们的第一个假设是,
细胞感觉到个体Toll受体类型表达的差异,以增加皮质张力,
降低细胞间粘附。我们已经开发了一种遗传系统,用于在单个细胞中表达单个受体。
我们将使用这些条带系统地表征和比较每种Toll受体类型对细胞的影响
形态学和鉴定调节细胞形状所必需的蛋白质结构域。我们的第二个假设是
在神经外胚层延伸过程中的快速细胞重排需要线粒体信号的变化,
驱动细胞骨架和连接重组。为了验证这一点,我们将使用多光子显微镜来观察
代谢辅因子的内源性自发荧光以量化在胚胎发育期间活胚胎中的细胞氧化还原状态
上皮重塑,然后使用功能获得和丧失技术来确定线粒体在上皮重塑中的作用。
融合和分裂在上皮重组中起作用。我们的第三个假设是Toll受体和GPCR信号转导
会聚以激活Rho激酶并触发神经外胚层中的细胞嵌入。我们会用得失-
功能分析,以确定这两个信号通路如何交叉控制皮质张力,细胞,
细胞粘附和上皮重塑过程中的线粒体动力学。成功完成这些
实验将使我们更全面地了解Toll受体在分子水平上的功能
以控制动态组织重塑期间的细胞生物力学和生物能量学。
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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{{ truncateString('Adam Christopher Pare', 18)}}的其他基金
Control of epithelial morphology and bioenergetics by Toll receptors during dynamic tissue remodeling
动态组织重塑过程中 Toll 受体对上皮形态和生物能的控制
- 批准号:
10357749 - 财政年份:2021
- 资助金额:
$ 31.15万 - 项目类别:
Control of epithelial morphology and bioenergetics by Toll receptors during dynamic tissue remodeling
动态组织重塑过程中 Toll 受体对上皮形态和生物能的控制
- 批准号:
10090750 - 财政年份:2021
- 资助金额:
$ 31.15万 - 项目类别:
Defining the molecular and cellular bases of tissue compartmentalization
定义组织区室化的分子和细胞基础
- 批准号:
10292120 - 财政年份:2021
- 资助金额:
$ 31.15万 - 项目类别:
Control of epithelial morphology and bioenergetics by Toll receptors during dynamic tissue remodeling
动态组织重塑过程中 Toll 受体对上皮形态和生物能的控制
- 批准号:
10574572 - 财政年份:2021
- 资助金额:
$ 31.15万 - 项目类别:
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