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NGF-TrkA Signaling in Load-Induced Bone Formation

负荷诱导骨形成中的 NGF-TrkA 信号传导

基本信息

批准号：
10555272
负责人：
Ryan Tomlinson
金额：
$ 34.32万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555272
关键词：
Adult Affinity Agonist Amides Axon Back Biomechanics Bone remodeling Calvaria Cues Data Development Disease Dissociation Ensure Focal Adhesion Kinase 1 Forelimb Health Hyperalgesia In Vitro Knockout Mice Knowledge Ligands Limb structure Location Mature Bone Mechanics Mediator Messenger RNA Microfluidics Mus NGFR Protein National Institute of Arthritis, and Musculoskeletal, and Skin Diseases Nerve Nerve Growth Factors Neurons Neuropeptides Neurotrophic Tyrosine Kinase Receptor Type 1 Osteoblasts Osteocytes Osteogenesis Pathogenicity Pathway interactions Periosteum Pharmaceutical Preparations Positioning Attribute Proteins Quantitative Reverse Transcriptase PCR Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Reporter Role Signal Pathway Signal Transduction System Testing Therapeutic Thermal Hyperalgesias Toll-like receptors Translational Research Validation WNT Signaling Pathway Western Blotting Work afferent nerve beta catenin bone bone cell bone mass conditional knockout experience fluid flow fracture risk improved in vivo inhibitor mechanical force mechanical load mouse model nerve injury neurotransmission osteogenic osteoprogenitor cell prevent programs receptor expression response skeletal small molecule tool transmission process

项目摘要

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.

项目总结/摘要几乎所有支配骨的感觉神经都表达1型神经营养酪氨酸激酶受体（TrkA），神经生长因子（NGF）的高亲和力受体。在成熟的骨骼中，这些特殊的感觉神经覆盖着骨膜呈密集的网状网络，占据生物力学信号的优先位置。然而，NGF在成骨细胞中的调节机制以及通过成骨细胞传递到骨的信号，感觉神经仍然未知。我们在这个项目中的主要目标是确定上游调解人，在应变适应性骨重建过程中NGF-TrkA信号传导的下游效应物。我们的核心假设是成熟成骨细胞中NF-κB信号的激活是NGF表达所必需的，机械负荷，这反过来又激活TrKA感觉神经，以提供支持负荷的成骨线索- 诱导骨形成。在具体目标1中，我们将确定成骨细胞中NGF表达的调节使用条件敲除小鼠的体外脉动流体流和体内前肢轴向压缩。在特定目的2，我们将通过分析mRNA和mRNA水平来确定促进负荷诱导骨形成的神经源性信号，在NGF-TrkA信号传导减弱的小鼠模型中，来自负载肢体的蛋白质，使用体外微流控平台在具体目标3中，我们将评估这种信号通路的潜在治疗应用增加成骨机械负荷后的骨积累而无痛觉过敏。总的来说，本研究将确定压力下NGF-TrkA信号传导的上游介质和下游效应物，适应性骨重建，并提供了一种潜在的治疗工具，用于利用该系统来改善骨骼健康此外，拟议的研究与NIAMS长期计划高度一致，我们的跨学科团队具有独特的优势来推进这些具体目标。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Leveraging Advancements in Tissue Engineering for Bioprinting Dental Tissues.

DOI：
10.1016/j.bprint.2021.e00153
发表时间：
2021-08
期刊：
Bioprinting
影响因子：
0
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：
0
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

The TrkA agonist gambogic amide augments skeletal adaptation to mechanical loading.