Admin Supplement: Role of Shh/Brachyury axis in the maintenance of the postnatal intervertebral disc
管理补充:Shh/Brachyury 轴在产后椎间盘维护中的作用
基本信息
- 批准号:10879520
- 负责人:
- 金额:$ 26.85万
- 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:2023-09-15 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffectAgeAgingAtlasesBrachyury proteinCatalogsCellsChronic low back painCodeCollectionData SetDatabasesDefectDevelopmentDifferentiation and GrowthEcosystemEmbryoEmbryonic StructuresFundingFutureGenesGeneticGenotype-Tissue Expression ProjectGoalsGrowthHealthHereditary DiseaseHeterozygoteHistologicHumanInjuryInternationalIntervertebral disc structureKnock-outKnockout MiceKnowledgeLearningLigandsMaintenanceMolecularMorphologyMusNatural regenerationOnline Mendelian Inheritance In ManPainPathologicPathologyPersonsPhenotypePopulationProcessProteinsPublishingQuality of lifeRejuvenationReportingResearchResourcesRoleSHH geneSignal TransductionSkeletonStandardizationStructureTestingTherapeuticUnited States National Institutes of HealthVertebral columnWorkage relatedchronic back paindata portaleffective therapyexperimental studygastrulationgene functiongenome wide association studygenome-wideinsightintervertebral disk degenerationknockout genemouse genomemouse modelmutantneonatal micenotochordnovelnucleus pulposusparent grantpathological agingpostnatalpostnatal developmentprogramsprotein protein interactionscreeningsexskeletalsmoothened signaling pathwaytargeted treatmenttranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY/ ABSTRACT
Mechanisms that regulate the formation and development of the intervertebral discs (IVDs) of the spine are not
well understood. Our current limited knowledge of the formation of the IVDs is built on genetic mouse models,
but much remains to be learned. Degenerative disc disease (DDD) is a leading cause of chronic low back pain
(cLBP), affecting the mobility and quality of life of millions of people worldwide, however, with no therapeutics or
cure. A better understanding of the cellular and molecular basis of the formation, development, and maintenance
of healthy IVD will help test the role of key developmental molecules in the regeneration of rejuvenation of the
IVDs. NIH Common Fund datasets generated by the Knockout Mouse Phenotyping Program (KOMP), a part of
the International Mouse Phenotyping Consortium (IMPC), is a genome-wide collection of mouse knockouts. The
goal of KOMP and IMPC is to generate a catalog of mammalian gene function, by knocking out every protein-
coding gene in the mouse genome, and deeply phenotype to understand its role in human health. A standardized
phenotyping pipeline is followed by the 21 research centers where the single-gene knockout mice are being
generated and phenotyped in both sexes. Our overarching hypothesis underlying this work is that a better
understanding of the genes and their network that regulate intervertebral disc (IVD, or disc) development and
maintenance, and can provide molecular insights into IVD pathologies. Previously we reported that BRA, a
critical developmental regulator is also expressed by postnatal nucleus pulposus (NP) cells of the IVDs and that
the expression of BRA declines with pathological IVD aging. NP cells are descendants of the embryonic
notochord, and our previous work showed the postnatal NP continues to act as the signaling center and regulate
the growth and differentiation of surrounding cells via SHH signaling. The goal of the proposed study is
to substantially leverage NIH Common Fund KOMP and GTEx portal datasets along with non-CF datasets like
STRING-db, OMIM, and publicly available GWAS datasets to screen novel genes required for IVD development
and maintenance. We will systematically prioritize genes to characterize the effect of their loss on IVD
development and maintenance using the single-KO knockouts generated and characterized by IMPC, that are
viable in heterozygous or homozygous conditions, have axial skeleton defects and are relevant to human health
using our screening pipeline. Completion of the proposed study will identify novel genes relevant to IVD, and
future mechanistic studies can test the hypothesis related to their specific roles in IVD formation, differentiation,
or health maintenance.
项目总结/摘要
调节脊柱椎间盘(IVD)形成和发育的机制并不
很好理解。我们目前对IVD形成的有限知识是建立在遗传小鼠模型上的,
但仍有许多东西有待了解。退行性椎间盘疾病(DDD)是慢性腰痛的主要原因
(cLBP),影响全球数百万人的流动性和生活质量,然而,没有治疗或
疗方更好地了解形成,发展和维持的细胞和分子基础
健康的IVD将有助于测试关键发育分子在再生中的作用。
体外诊断NIH共同基金数据集由敲除小鼠表型分析计划(KOMP)生成,
国际小鼠表型鉴定协会(IMPC)是小鼠敲除的全基因组集合。的
KOMP和IMPC的目标是通过敲除每一种蛋白质,
小鼠基因组中的编码基因,并深入表型,了解其在人类健康中的作用。标准化
表型分析管道之后是21个研究中心,在那里单基因敲除小鼠正在进行
在两性中产生和表型化。这项工作的首要假设是,
了解调控椎间盘(IVD或椎间盘)发育的基因及其网络,
维持,并且可以提供对IVD病理学的分子见解。此前我们曾报道,
出生后IVD的髓核(NP)细胞也表达关键的发育调节因子,
BRA的表达随着病理性IVD的增龄而下降。NP细胞是胚胎干细胞的后代。
我们以前的工作表明,出生后的NP继续作为信号中心,
通过SHH信号传导促进周围细胞的生长和分化。拟议研究的目标是
充分利用NIH共同基金KOMP和GTEx门户数据集沿着非CF数据集,
STRING-db、OMIM和公开可用的GWAS数据集,用于筛选IVD开发所需的新基因
和维护我们将系统地优先考虑基因,以表征其丢失对IVD的影响
使用IMPC生成和表征的单KO敲除进行开发和维护,
可在杂合或纯合条件下存活,具有中轴骨骼缺陷并与人类健康相关
使用我们的筛选管道。完成拟议的研究将确定与IVD相关的新基因,
未来的机制研究可以检验与它们在IVD形成,分化,
或健康维护。
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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Chitra L Dahia其他文献
Chitra L Dahia的其他文献
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{{ truncateString('Chitra L Dahia', 18)}}的其他基金
Role of Developmental Signaling Pathways in Maintenance of Spinal Discs
发育信号通路在椎间盘维护中的作用
- 批准号:
10305941 - 财政年份:2021
- 资助金额:
$ 26.85万 - 项目类别:
Role of Developmental Signaling Pathways in Maintenance of Spinal Discs
发育信号通路在椎间盘维护中的作用
- 批准号:
10609916 - 财政年份:2021
- 资助金额:
$ 26.85万 - 项目类别:
Role of Shh/Brachyury axis in the maintenance of the postnatal intervertebral disc
Shh/Brachyury 轴在产后椎间盘维持中的作用
- 批准号:
10596619 - 财政年份:2021
- 资助金额:
$ 26.85万 - 项目类别:
Role of Developmental Signaling Pathways in Maintenance of Spinal Discs
发育信号通路在椎间盘维护中的作用
- 批准号:
10469481 - 财政年份:2021
- 资助金额:
$ 26.85万 - 项目类别:
Role of Shh/Brachyury axis in the maintenance of the postnatal intervertebral disc
Shh/Brachyury 轴在产后椎间盘维持中的作用
- 批准号:
10433845 - 财政年份:2021
- 资助金额:
$ 26.85万 - 项目类别:
A Wnt/Shh signaling loop controls intervertebral disc growth and differentiation
Wnt/Shh 信号环路控制椎间盘生长和分化
- 批准号:
8759103 - 财政年份:2014
- 资助金额:
$ 26.85万 - 项目类别:
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