Neuroskeletal crosstalk in load-induced bone formation

负荷诱导骨形成中的神经骨骼串扰

基本信息

批准号：
10609816
负责人：
Alec T Beeve
金额：
$ 5.02万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10609816
关键词：
ACTL6B gene Affect Affinity Anabolism Anorexia Axon Biology Biomechanics Bone Diseases Bone Surface Cell physiology Cell secretion Complex Cues Data Denervation Development Diabetes Mellitus Disease Efferent Neurons Environment Esthesia Exercise Exhibits Fellowship Femur Fluorescent Dyes Foundations Functional disorder Future Gatekeeping Gene Expression Genes Goals Health Hindlimb Histologic Histology Homeostasis Human Image Image Analysis Imaging Techniques Immunohistochemistry Impairment In Situ Hybridization Laboratory Research Limb structure Literature Maps Mature Bone Mentors Mentorship Metabolism Methods Minerals Modeling Modification Multiple Sclerosis Mus NGFR Protein Nerve Nerve Fibers Nerve Growth Factors Nervous System Neurons Neuropathy Neurotrophic Tyrosine Kinase Receptor Type 1 Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Outcome Patients Pattern Periodicity Periosteum Peripheral Nerves Physiologic calcification Physiology Play Population Pre-Clinical Model Protocols documentation Regimen Reporter Research Role Running Sensory Signal Induction Signal Transduction Skeleton Spinal cord injury Surface Technical Expertise Techniques Testing Therapeutic Effect Training Treatment Efficacy Universities Up-Regulation Visualization WNT1 gene Washington Weight-Bearing state Work bone bone cell bone health bone loss bone mass career chemotherapy density design fluorexon fracture risk improved in vivo long bone mechanical load mechanical stimulus medical schools mineralization nerve supply neuron loss neuroregulation neurotransmission neurotransmitter release novel response skeletal skeletal disorder tibia tool

项目摘要

PROJECT SUMMARY/ABSTRACT Peripheral nerve dysfunction is associated with skeletal fragility in humans and in preclinical models. While proprioceptive deficits play a significant role in increased fracture risk, loss of local innervation may deplete bone of neuronal factors critical for skeletal homeostasis. This presents new challenges for maintaining bone health in patients with neuropathy and those undergoing nerve-modifying treatments. Specifically, it may affect the therapeutic efficacy of weight-bearing exercise. Mechanically loading bone through exercise is a well-established requirement for bone health. Compression of long bones results in skeletal remodeling to increase strength. In addition, bone cells secrete neurotrophic cues after loading that may facilitate nerve sprouting towards the skeleton, modifying endogenous skeletal innervation patterns. Considering this emerging role of nerves in skeletal metabolism, local neuroskeletal signaling may be required to facilitate load-induced bone formation. The central goal of this proposal is to investigate the plasticity and necessity of neuroskeletal crosstalk in the anabolic response of bone to compressive loading. To accomplish this, the proposed research is divided into two aims. In Aim 1, novel neuroskeletal niches involved in load-induced bone formation will be defined. To investigate how native neuroskeletal niches are modified during skeletal adaptation, a 5-day regimen of in vivo axial compression will be conducted on mice to induce lamellar bone formation, followed by histology and imaging of the tibia. Nerves in bone will be mapped using a novel pan-neuronal Baf53b-Ai9 reporter mouse and immunostaining for nerve subtypes. In addition, local Ngf and Wnt1 gene expression will be mapped in relation to defined neuroskeletal niches using in situ hybridization. To study the spatial localization and relative quantities of axons, mineralizing surface, and gene expression, a novel image analysis workflow (RadialQuant) will be used. In Aim 2, the necessity of these neuroskeletal niches for load-induced bone formation will be evaluated. To test this, a model of tibial denervation will be developed by evaluating neuronal loss after one-week of femoral and/or sciatic neurectomy using the imaging techniques employed in Aim 1. To test the necessity of innervation in skeletal adaptation, the hindlimb will be denervated accordingly prior to cyclic axial compression as in Aim 1. Techniques from Aim 1 will be used isolate the effect of loading and denervation on axon density, mineral apposition, and gene expression. The long-term career goal of the applicant is to run an independent research laboratory. In addition to the research plan, the training plan is designed to achieve this goal through development of new technical skills, mentorship, and critical synthesis of literature. The two-year fellowship will be conducted at the Washington University School of Medicine under the mentorship of Dr. Erica Scheller and Dr. Matthew Silva, with expertise in neuroskeletal biology and bone biomechanics, respectively.

项目摘要/摘要周围神经功能障碍与人类和临床前模型中的骨骼脆弱性有关。虽然本体感知缺陷在增加的骨折风险中起着重要作用，但局部神经的丧失可能神经元因子的耗尽骨骼对骨骼稳态至关重要。这提出了维持的新挑战神经病患者的骨骼健康和接受神经修改治疗的患者。具体来说，它可能影响体重运动的治疗功效。通过锻炼机械加载骨头是公认的骨骼健康需求。长骨的压缩导致骨骼重塑为增加强度。此外，骨细胞在加载后分泌神经营养的提示，以促进神经向骨骼发芽，修饰内源性骨骼神经支配模式。考虑这一新兴神经在骨骼代谢中的作用，可能需要局部神经骨骼信号传导以促进负载诱导骨形成。该提案的核心目标是研究神经骨骼的可塑性和必要性骨骼对压缩负荷的合成代谢响应中的串扰。为此，拟议的研究分为两个目标。在AIM 1中，参与负载诱导骨形成的新型神经骨骼壁ches将是定义。为了调查在骨骼适应期间如何修饰天然神经骨骼壁nike，为期5天体内轴向压缩方案将在小鼠上进行诱导层状骨形成，然后进行胫骨的组织学和成像。骨头的神经将使用新型的泛神经元BAF53B-AI9映射记者小鼠和神经亚型的免疫染色。此外，局部NGF和WNT1基因表达将使用原位杂交与定义的神经骨骼壁ni有关。研究空间轴突的定位和相对量，矿化表面和基因表达，一种新的图像分析将使用工作流（径向）。在AIM 2中，这些神经骨骼壁ches的必要性是负载诱导的将评估骨形成。为了测试这一点，将通过评估来开发胫骨修神经模型使用成像技术的股骨和/或坐骨神经切除术一周后的神经元损失目的1。为了测试骨骼适应中的神经支配的必要性，后肢将被剥夺在AIM 1中（AIM 1）中的循环轴向压缩之前，AIM 1的技术将被隔离到负载的效果以及关于轴突密度，矿物含量和基因表达的神经保护。长期职业目标申请人应运营一个独立的研究实验室。除了研究计划外，培训计划是旨在通过发展新的技术技能，指导和关键综合来实现这一目标文学。这项为期两年的奖学金将在华盛顿大学医学院进行 Erica Scheller博士和Matthew Silva博士的指导，具有神经骨骼生物学和骨骼的专业知识生物力学分别。