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：
9894734
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894734
关键词：
Adult Affinity Agonist Amides Axon Back Biomechanics Bone remodeling Calvaria Cues Data Development Disease Ensure Focal Adhesion Kinase 1 Forelimb Health Hyperalgesia In Vitro Knockout Mice Knowledge Ligands Limb structure Location Mature Bone Mechanics Mediator of activation protein 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 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 base beta catenin bone bone cell bone mass conditional knockout experience fluid flow fracture risk improved in vivo inhibitor/antagonist mechanical force mechanical load mouse model nerve injury neurotransmission osteogenic osteoprogenitor cell prevent programs receptor expression response skeletal small molecule tool

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.

项目概要/摘要几乎所有支配骨骼的感觉神经都表达神经营养性酪氨酸激酶受体 1 型 (TrkA)，在成熟的骨骼中，这些特殊的感觉神经覆盖着神经生长因子（NGF）的高亲和力受体。骨膜呈致密的网状网络，占据生物力学信号传导的优先位置。然而，NGF 在成骨细胞中的调节机制以及通过我们在这个项目中的主要目标是确定上游介质和感觉神经。 NGF-TrkA 信号在应变适应性骨重塑过程中的下游影响我们的中心假设是。成熟成骨细胞中 NF-κB 信号的激活是 NGF 表达的必要条件机械负荷，进而激活 TrKA 感觉神经，提供支持负荷的成骨信号在具体目标 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。目标 2，我们将通过分析 mRNA 和 NGF-TrkA 信号传导减弱的小鼠模型中负载四肢的蛋白质，并使用体外验证在具体目标 3 中，我们将评估该信号通路的潜在治疗应用。在没有痛觉过敏的情况下增加成骨机械负荷后的骨生成。这项研究将定义应变过程中 NGF-TrkA 信号传导的上游介质和下游效应器适应性骨重塑，并为利用该系统改善骨骼提供潜在的治疗工具此外，拟议的研究与 NIAMS 长期计划以及我们的研究高度一致。跨学科团队具有独特的优势来推进这些具体目标。