TGFbeta in the pathology and development of the spine
TGFbeta in the pathology and development of the spine
批准号:
10731938
负责人:
Rosa A. Serra
金额:
$32.15万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-04 至 2028-06-30
关键词:
AddressAffectBinding ProteinsBiological AssayBiological ProcessBiologyCell Differentiation processCellsCervicalChIP-seqChick EmbryoCompetenceConnective TissueDNA BindingDataDegenerative DisorderDevelopmentDiseaseDominant-Negative MutationDrug TargetingElementsEmbryoEmbryonic DevelopmentEngineeringFibrocartilagesFoundationsFutureGenesGenetic PolymorphismGenetically Engineered MouseGenomicsGrowthHomeostasisIntervertebral disc structureLabelLaboratoriesLigamentsLigandsMaintenanceMapsMediatingMolecularMolecular BiologyMotionMovementMusMuscleMutationNatural regenerationNervePathologyPathway interactionsPatternPreventionProcessPublishingRegulationResponse ElementsRoleSclerotomeSignal PathwaySignal TransductionSignaling ProteinSkeletonSomitesSpinal DiseasesSpinal OsteophytosisTGFB1 geneTGFB3 geneTGFBR2 geneTechniquesTechnologyTendon structureTestingTissue EngineeringTissue imagingTissuesTransforming Growth Factor betaTransgenic MiceVertebral columnexperimental studymRNA Expressionmembermouse modelpermissivenessposterior longitudinal ligament ossificationpostnatalprogenitorreceptorregenerativerepairedscleraxisscoliosisskeletalskeletal tissuesternocostal jointtranscription factortranscriptome sequencing
中文摘要
项目摘要。
这项研究的长期目标是了解参与发展和维持的信号,
轴向骨架,可以告知再生和工程策略。Tgfb超家族的成员是
调节骨骼生物学许多方面的分泌信号蛋白。多态性和突变
调节Tgfb活性的基因与脊柱病理学有关。它也被证明使用
Tgfbr 2是纤维组织发育和维持所必需的基因工程小鼠,
脊柱包括椎间盘的纤维环、韧带和肌腱。先前结果
在我的实验室获得的结果表明,Tgfb调节细胞命运的决定,在硬结,胚胎
脊椎中结缔组织的祖细胞。在本申请中,我们提出解决具有指导意义的
Tgfb调节脊柱纤维组织胚胎形成的机制。另外我们
我建议解决硬节再分割的问题,这是一个创造空间的胚胎过程。
脊柱中组织的组织结构。重新分段的改变预计将改变
细胞分化,影响许可信号和对指导信号作出反应的能力,
决定细胞命运最后,使用我实验室开发的小鼠模型,
Tgfb如何在出生后纤维环中维持纤维特性的机制。整体
该建议的目的是:1)确定Tgfb用于产生纤维组织的信号通路,
2)绘制重新分段的过程,并确定
Tgfb介导的调节机制和3)了解Tgfb如何维持纤维环
出生后这里所描述的实验将提供有关发育的机理信息,
维护中轴骨架,并为未来的再生和工程策略提供基础
在脊椎上
英文摘要
Project Summary.
The long-term objective of this study is to understand signals involved in development and maintenance of the
axial skeleton that can inform regenerative and engineering strategies. Members of the Tgfb superfamily are
secreted signaling proteins that regulate many aspects of skeletal biology. Polymorphisms and mutations in
genes that regulate Tgfb activity have been associated with pathology in the spine. It’s also been shown using
genetically engineered mice that Tgfbr2 is required for development and maintenance of the fibrous tissues in
the spine including the annulus fibrosus of the intervertebral disc, ligaments, and tendon. Previous results
obtained in my laboratory indicate that Tgfb regulates cell fate decisions in the sclerotome, the embryonic
progenitor of the connective tissues in the spine. In this application, we propose to address the instructive
mechanisms whereby Tgfb regulates embryonic formation of fibrous tissues in the spine. In addition, we
propose to address the problem of sclerotome resegmentation, an embryonic process that creates the spatial
organization of tissues in the spine. Alterations in resegmentation would be expected to alter the context in
which cells differentiate, affecting permissive signals and competence to respond to instructive signals that
govern cell fate decisions. Finally, using a mouse model developed in my laboratory, we will start to determine
the mechanisms of how Tgfb acts to maintain fibrous character in the postnatal annulus fibrosus. The overall
aims of this proposal are to: 1) Determine the signaling pathways used by Tgfb to generate fibrous tissues of
the spine during embryonic development; 2) To map the process of resegmentation and determine the
mechanism of Tgfb-mediated regulation and 3) To understand how Tgfb maintains annulus fibrosus
postnatally. The experiments described here will provide mechanistic information about development and
maintenance of the axial skeleton and provide a foundation for future regeneration and engineering strategies
in the spine.
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