Mechanobiology of fracture healing during skeletal disuse

骨骼废用期间骨折愈合的力学生物学

基本信息

批准号：
10723764
负责人：
Evan G Buettmann
金额：
$ 11.21万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723764
关键词：
Acute Affect Aging Attenuated Award Bed rest Bioinformatics Biomechanics Blood Vessels Bone Injury Bone Regeneration Bone callus Burn injury Cell Lineage Cells Clinical Coupling Data Development Diabetes Mellitus Disease Down-Regulation Electric Stimulation Environment Flow Cytometry Fracture Genes Genetic Genetic Engineering Grant Health Hindlimb Suspension Hormonal Impairment In Vitro Incidence Individual Intervention Knowledge Light Mechanics Mediator Mentors Modality Modeling Molecular Mus Muscle Muscle Contraction Muscle Weakness Muscular Atrophy Musculoskeletal Obesity Osteoblasts Osteocytes Osteogenesis Outcome Pain Paralysed Pathology Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Physical Rehabilitation Physiologic pulse Population Pre-Clinical Model Process Proteins Recovery Regimen Rehabilitation therapy Reporting Research Risk Role Signal Transduction Skeletal Muscle Space Flight Techniques Testing Tissues Training Transcript Transcriptional Coactivator with PDZ-Binding Motif Verteporfin Weight-Bearing state Work angiogenesis bone bone cell bone fracture repair bone healing bone loss bone mass bone repair career cell type deprivation fall risk falls fracture risk fragility fracture healing high risk improved in vivo insight limb bone mechanical load mortality mouse model muscle form muscle strength optogenetics osteoclastogenesis osteogenic osteoimmunology protein activation radiological imaging reduced muscle mass repaired skeletal skeletal muscle wasting skills stem cell proliferation targeted treatment transcriptome sequencing virtual

项目摘要

PROJECT SUMMARY/ABSTRACT Decreased muscle and bone mass and strength resulting from musculoskeletal unloading (disuse osteosarcopenia) has long been associated with increased fracture risk, impaired bone healing and worse patient outcomes. Current disease modifying drugs are centered primarily on bone targeted therapies (anti- resorptives and PTH), and remain ineffective at targeting muscle loss that appears crucial for healthy bone repair and reducing fall risk. Although early reambulation and physical rehabilitation following bone injury is known to be beneficial for fracture healing and muscle recovery, there remains a gap in our knowledge of the appropriate mechanical loading regimens following osteosarcopenic fracture due to limited knowledge of how disuse affects fracture healing mechanobiology. In preliminary work, we have a developed a murine model of fracture healing during disuse by hindlimb unloading, with and without remobilization. This model recapitulates many clinical features of bone repair during disuse (decreased skeletal muscle mass, decreased radiographical callus formation) with new findings such as altered callus vascularity and osteoclastogenesis that are attenuated with reambulation. The aims outlined in this proposal seek to greatly expand upon our preliminary studies by using non-invasive loading modalities targeting muscle and or bone directly to determine the critical cellular and molecular mediators of callus mechanobiology during disuse. In the mentored K99 portion of this grant, we will utilize non-invasive optogenetics and direct tibial loading to determine optimal mechanical inputs to increase callus healing, biomechanical integrity, and muscle mass during disuse (Aim 1). Next using high-throughput techniques (RNAseq and flow cytometry), we will investigate the potential underlying mechanisms by which non-invasive loading affects callus mechanobiology during disuse (Aim 2). During the R00 phase, Dr. Buettmann will leverage recent mechanistic findings to determine the conditional role of mechanosensitive molecules in coordinating load-induced alterations in fracture healing during disuse (Aim 3). These insights will help bridge a significant gap in our understanding of how disuse alters callus mechanobiology and how mechanically-regulated molecules can be leveraged to improve fracture healing and rehabilitation in osteosarcopenic “high risk” patients. These findings, owing to the preclinical model’s translatability, could also have far-reaching implications for other pathologies associated with impaired fracture healing and altered mechanosensation such as aging, obesity/diabetes, and hormonal deprivation. Dr. Buettmann has assembled a mentoring team and collaborators with expertise in bone regeneration/osteoimmunology (Drs. Olivares-Navarrete), optogenetics and muscle-bone mechanoregulation (Dr. Megan Killian), musculoskeletal bioinformatics (Dr. Charles Farber), biomechanics (Dr. Hannah Dailey) and mechanobiology (Dr. Henry Donahue). This project will prepare Dr. Buettmann for an independent research career in musculoskeletal research by acquiring the necessary training and research data for an R01 equivalent award.

项目概要/摘要由于肌肉骨骼卸载（废用）导致肌肉和骨骼质量和强度下降骨肌减少症）长期以来一直与骨折风险增加、骨愈合受损以及更糟糕的情况有关目前的疾病缓解药物主要集中在骨靶向治疗（抗骨治疗）上。再吸收剂和 PTH），并且在针对对健康骨骼至关重要的肌肉损失方面仍然无效尽管骨损伤后的早期重新融入和身体康复是重要的。已知有益于骨折愈合和肌肉恢复，但我们对它的了解仍然存在差距由于对如何进行骨肌减少性骨折的了解有限，因此需要采取适当的机械负荷方案在前期工作中，我们开发了一种小鼠模型。废弃期间通过后肢卸载（有或没有再活动）的骨折愈合。废用期间骨修复的许多临床特征（骨骼肌质量减少，放射照相愈伤组织形成）以及新发现，例如愈伤组织血管分布和破骨细胞生成该提案中概述的目标旨在极大地扩展我们的范围。通过使用直接针对肌肉和/或骨骼的非侵入性加载方式进行初步研究以确定在指导的 K99 中，愈伤组织机械生物学的关键细胞和分子介质。在这笔赠款的一部分中，我们将利用非侵入性光遗传学和直接胫骨负重来确定最佳机械输入以增加废用期间的愈伤组织愈合、生物力学完整性和肌肉质量（目标 1）。接下来使用高通量技术（RNAseq 和流式细胞术），我们将研究潜在的非侵入性加载影响废弃期间愈伤组织力学生物学的潜在机制（目标 2）。在 R00 阶段，Buettmann 博士将利用最近的机制发现来确定条件机械敏感分子在协调废弃期间骨折愈合中负载引起的变化中的作用（目标 3）。这些见解将有助于弥合我们对废用如何改变愈伤组织的理解上的重大差距。机械生物学以及如何利用机械调节分子来改善骨折愈合和这些发现归功于临床前模型的结果。可翻译性，也可能对与骨折受损相关的其他病理产生深远的影响愈合和机械感觉改变，如衰老、肥胖/糖尿病和激素缺乏。 Buettmann 组建了一支具有骨科专业知识的指导团队和合作者再生/骨免疫学（Olivares-Navarrete 博士）、光遗传学和肌骨机械调节（Megan Killian 博士）、肌肉骨骼生物信息学（Charles Farber 博士）、生物力学（Hannah Dailey 博士）和机械生物学（Henry Donahue 博士）。该项目将为 Buettmann 博士的独立研究做好准备。通过获取 R01 所需的培训和研究数据，从事肌肉骨骼研究的研究生涯同等奖励。