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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：
10464348
负责人：
Alec T Beeve
金额：
$ 4.93万
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/10464348
关键词：
ACTL6B gene Affect Affinity Anabolism Axon Biology Biomechanics Bone Diseases Bone Surface Cell physiology Complex Cues Data Denervation Development Diabetes Mellitus Disease Efferent Neurons Environment Esthesia Exercise Exhibits Fellowship 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 structure Neurons Neuropathy Neurotrophic Tyrosine Kinase Receptor Type 1 Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Outcome Patients Pattern Periodicity Periosteum Peripheral Nerves Physiology Play Population Pre-Clinical Model Protocols documentation Regimen Reporter Research Role Running Sensory Signal Transduction Skeleton Spinal cord injury Surface Technical Expertise Techniques Testing Therapeutic Effect Training Treatment Efficacy Universities Up-Regulation WNT1 gene Washington Weight-Bearing state Work base bone bone cell bone health bone loss career chemotherapy density design fluorexon fracture risk fragility fracture 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.

项目总结/文摘