Role of force regulated nuclear structure in expression of osteogenesis
力调节核结构在成骨表达中的作用
基本信息
- 批准号:10632101
- 负责人:
- 金额:$ 45.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:ActinsAddressAffectArchitectureBiomechanicsBone MarrowCell LineageCell NucleusCellsChromatinCytoplasmCytoskeletonDNADNA RepairDataEZH2 geneEpigenetic ProcessEuchromatinExerciseF-ActinFocal AdhesionsGene ActivationGene ExpressionGene SilencingGene TargetingGenesGenomeHeterochromatinLamin B1LaminsLinkMarrowMeasuresMechanicsMediatingMesenchymalMesenchymal Stem CellsModelingNatureNuclearNuclear EnvelopeNuclear ImportNuclear PoreNuclear StructureNuclear TranslocationOsteoblastsOsteogenesisPPAR gammaPhysical condensationPolymersPositioning AttributeProliferatingPublishingRegulator GenesRegulatory PathwayRoleSignal InductionSignal PathwaySignal TransductionSmall Interfering RNAStimulusStressStromal CellsStructureTestingVariantbeta cateninbonebone marrow mesenchymal stem cellepigenetic regulationexperiencehistone methylationinhibitorknock-downlipid biosynthesisloss of functionmechanical forcemechanical stimulusnovelnuclear transferosteogenicpolymerizationpreventprogramspromoterresponsestemstem cell differentiationstem cell fatestem cellsstemnesstranscription factortranscriptometranscriptome sequencing
项目摘要
Abstract: Role of force regulated nuclear structure in expression of osteogenesis
Bone marrow mesenchymal stem cells (MSC) exist in a multipotential state, where osteogenic
and adipogenic genomes are silenced in heterochromatin at the inner nuclear leaflet. Activating
the osteogenic differentiation program involves multiple regulatory factors, including physical
force, which is generated in the marrow space during dynamic exercise. MSC experience
mechanical force through their cytoskeletal attachments to substrate, inducing signaling that
alters gene expression. We showed that intranuclear actin structures are affected by changes in
the cytoplasmic cytoskeleton, and direct changes in intranuclear actin due to knock down of
nuclear restricted mDia2 (preventing intranuclear actin polymerization) exert profound regulatory
control on gene expression. Further, although both dynamic and static mechanical force activate
RhoA to control formation of the actin cytoskeleton, the nature of these forces appear to have
widely variant effects on gene expression – dynamic force inhibits adipogenesis and promotes
multipotentiality, while static force is associated with osteogenesis. Dynamic versus static
applications may affect gene expression through generating different forces on the nucleus,
affecting nuclear structure and nuclear access of the mechanoresponders, Yap and β-catenin.
We here hypothesize that nuclear structure, modified by force activated actin polymerization,
contributes to selective MSC differentiation and fate. To address this hypothesis, we propose to
define how cellular actin structure resulting from dynamic or static mechanical force differentially
regulate nuclear architecture and gene expression. In SA1 we will find if dynamic and static strain
differentially modify nuclear architecture (F-actin and lamin structure, nucleoli size and spacing,
cell and nuclear stiffness and FISH localization of Runx2). Our data shows that loss of intranuclear
actin polymerization decreases lamin B1 at the inner nuclear leaflet, thus we will find if force alters
osteogenic gene silencing through lamins, and if alterations in formin mDia2 or laminB1 modulate
heterochromatization of the osteogenic genome. In SA2 we will ask if dynamic and static force
differentially regulate nuclear entry of Yap or β-catenin, and relate cytoskeletal stress transfer to
the nuclear membrane to changes in nuclear access of these molecules. Unbiased RNAseq will
allow us to compare gene expression after dynamic vs static force and ask if nuclear Yap and β-
catenin are critical. Lastly in SA3 we determine if intranuclear actin structure directly controls
access to the osteogenic genome. We will define nuclear structure after mDia2 knock down
(decrease intranuclear F-actin, induces osteogenesis), mDia1 knock down (decreasing
cytoplasmic F-actin) and altering secondary actin branching (induces adipogenesis). In these
conditions we will relate nuclear structure to activation of Runx2 and PPARγ cistromes.
Upon completion of our objectives we will be able to establish how mechanical forces and
nuclear actin polymerization control epigenetic induction of osteogenesis and regulate nuclear
transfer of YAP and β-catenin.
摘要:力调控核结构在成骨过程中的作用
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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Janet E Rubin其他文献
Janet E Rubin的其他文献
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{{ truncateString('Janet E Rubin', 18)}}的其他基金
Role of force regulated nuclear structure in expression of osteogenesis
力调节核结构在成骨表达中的作用
- 批准号:
10401789 - 财政年份:2020
- 资助金额:
$ 45.78万 - 项目类别:
Mechanical regulation of cytoskeleton guides beta-catenin effect on MSC fate
细胞骨架的机械调节引导β-连环蛋白对MSC命运的影响
- 批准号:
8875844 - 财政年份:2015
- 资助金额:
$ 45.78万 - 项目类别:
Mechanical regulation of cytoskeleton guides beta-catenin effect on MSC fate
细胞骨架的机械调节引导β-连环蛋白对MSC命运的影响
- 批准号:
9252230 - 财政年份:2015
- 资助金额:
$ 45.78万 - 项目类别:
Mechanical regulation of cytoskeleton guides beta-catenin effect on MSC fate
细胞骨架的机械调节引导β-连环蛋白对MSC命运的影响
- 批准号:
9460430 - 财政年份:2015
- 资助金额:
$ 45.78万 - 项目类别:
Mechanical regulation of cytoskeleton guides beta-catenin effect on MSC fate
细胞骨架的机械调节引导β-连环蛋白对MSC命运的影响
- 批准号:
9042946 - 财政年份:2015
- 资助金额:
$ 45.78万 - 项目类别:
Mechanical Control of Mesenchymal Stem Cell Lineage Allocation
间充质干细胞谱系分配的机械控制
- 批准号:
8461687 - 财政年份:2010
- 资助金额:
$ 45.78万 - 项目类别:
Mechanical Control of Mesenchymal Stem Cell Lineage Allocation
间充质干细胞谱系分配的机械控制
- 批准号:
8067137 - 财政年份:2010
- 资助金额:
$ 45.78万 - 项目类别:
Mechanical Control of Mesenchymal Stem Cell Lineage Allocation
间充质干细胞谱系分配的机械控制
- 批准号:
8271289 - 财政年份:2010
- 资助金额:
$ 45.78万 - 项目类别:
Mechanical Control of Mesenchymal Stem Cell Lineage Allocation
间充质干细胞谱系分配的机械控制
- 批准号:
7889037 - 财政年份:2010
- 资助金额:
$ 45.78万 - 项目类别:
ORGANIZATION OF MECHANICAL SIGNALS VIA MEMBRANE SCAFFOLD
通过膜支架组织机械信号
- 批准号:
6986682 - 财政年份:2005
- 资助金额:
$ 45.78万 - 项目类别:
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