NGF-TrkA Signaling in Load-Induced Bone Formation
NGF-TrkA Signaling in Load-Induced Bone Formation
批准号:
10555272
负责人:
Ryan Tomlinson
金额:
$34.32万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
未结题
起止时间:
2019-04-01 至 2025-01-31
关键词:
AdultAffinityAgonistAmidesAxonBackBiomechanicsBone remodelingCalvariaCuesDataDevelopmentDiseaseDissociationEnsureFocal Adhesion Kinase 1ForelimbHealthHyperalgesiaIn VitroKnockout MiceKnowledgeLigandsLimb structureLocationMature BoneMechanicsMediatorMessenger RNAMicrofluidicsMusNGFR ProteinNational Institute of Arthritis, and Musculoskeletal, and Skin DiseasesNerveNerve Growth FactorsNeuronsNeuropeptidesNeurotrophic Tyrosine Kinase Receptor Type 1OsteoblastsOsteocytesOsteogenesisPathogenicityPathway interactionsPeriosteumPharmaceutical PreparationsPositioning AttributeProteinsQuantitative Reverse Transcriptase PCRReceptor Protein-Tyrosine KinasesReceptor SignalingRegulationReporterRoleSignal PathwaySignal TransductionSystemTestingTherapeuticThermal HyperalgesiasToll-like receptorsTranslational ResearchValidationWNT Signaling PathwayWestern BlottingWorkafferent nervebeta cateninbonebone cellbone massconditional knockoutexperiencefluid flowfracture riskimprovedin vivoinhibitormechanical forcemechanical loadmouse modelnerve injuryneurotransmissionosteogenicosteoprogenitor cellpreventprogramsreceptor expressionresponseskeletalsmall moleculetooltransmission process
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
Nearly all of the sensory nerves that innervate bone express neurotrophic tyrosine kinase receptor type 1 (TrkA),
the high affinity receptor for nerve growth factor (NGF). In mature bone, these specialized sensory nerves blanket
the periosteum in a dense mesh-like network, occupying a preferential location for biomechanical signaling.
However, the mechanism by which NGF is regulated in the osteoblast and the signals transmitted to bone by
sensory nerves remain unknown. Our main objective in this project is to determine the upstream mediators and
downstream effectors of NGF-TrkA signaling during strain adaptive bone remodeling. Our central hypothesis is
that activation of NF-κB signaling in mature osteoblasts is required for the expression of NGF in response to
mechanical load, which in turn activates TrKA sensory nerves to provide osteogenic cues that support load-
induced bone formation. In Specific Aim 1, we will determine the regulation of NGF expression in osteoblasts
using in vitro pulsatile fluid flow and in vivo forelimb axial compression of conditional knockout mice. In Specific
Aim 2, we will identify nerve-derived signals that promote load-induced bone formation by analyzing mRNA and
protein from loaded limbs in mouse models of diminished NGF-TrkA signaling, with validation using an in vitro
microfluidic platform. In Specific Aim 3, we will assess a potential therapeutic application of this signaling pathway
to increase bone accrual following osteogenic mechanical loading without hyperalgesia. In total, the results from
this study will define the upstream mediators and downstream effectors of NGF-TrkA signaling during strain
adaptive bone remodeling and provide a potential therapeutic tool for leveraging this system to improve skeletal
health. Moreover, the proposed studies are highly aligned with the NIAMS Long-Range Plan, and our
interdisciplinary team is uniquely positioned to advance these specific aims.
期刊论文(4)
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科研奖励(0)
会议论文
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DOI:
10.1016/j.bprint.2021.e00153
发表时间:
2021-08
期刊:
Bioprinting
影响因子:
--
作者:
[Devin Grace Morrison;R. Tomlinson]
通讯作者:
Devin Grace Morrison;R. Tomlinson
Circulating inflammatory cytokines alter transcriptional activity within fibrotic tissue of Dupuytren's disease patients.
循环炎性细胞因子改变掌腱膜挛缩症患者纤维化组织内的转录活性。
DOI:
10.1002/jor.25059
发表时间:
2022
期刊:
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
影响因子:
--
作者:
[Wang,MarkL, Rajpar,Ibtesam, Ruggiero,NicholasA, Fertala,Jolanta, Steplewski,Andrzej, Beredjiklian,PedroK, Rivlin,MichaelR, Chen,Yong, Feldman,GeorgeJ, Fertala,Andrzej, Tomlinson,RyanE]
通讯作者:
Tomlinson,RyanE
DOI:
10.1016/j.bone.2021.115908
发表时间:
2021-06
期刊:
Bone
影响因子:
4.1
作者:
[Fioravanti G, Hua PQ, Tomlinson RE]
通讯作者:
Tomlinson RE
DOI:
10.1016/j.semcdb.2021.05.001
发表时间:
2022-03
期刊:
Seminars in cell & developmental biology
影响因子:
7.3
作者:
[Rajpar I, Tomlinson RE]
通讯作者:
Tomlinson RE
NGF-TrkA Signaling in Dental Implant Osseointegration and Osseoperception
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批准号:9882982
-
项目类别:
-
资助金额:$15.6万
-
财政年份:2019
-
负责人:Ryan Tomlinson
-
依托单位:
NGF-TrkA Signaling in Load-Induced Bone Formation
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批准号:9894734
-
项目类别:
-
资助金额:$34.32万
-
财政年份:2019
-
负责人:Ryan Tomlinson
-
依托单位:
NGF-TrkA Signaling in Load-Induced Bone Formation
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批准号:10113356
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项目类别:
-
资助金额:$33.29万
-
财政年份:2019
-
负责人:Ryan Tomlinson
-
依托单位:
NGF-TrkA Signaling in Load-Induced Bone Formation
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批准号:10335219
-
项目类别:
-
资助金额:$33.98万
-
财政年份:2019
-
负责人:Ryan Tomlinson
-
依托单位:
海外基金