Multi-scale MRI Assessment of Bone Quality and Function in a Chronic Rat Spinal Cord Injury Model

慢性大鼠脊髓损伤模型中骨质量和功能的多尺度 MRI 评估

• 批准号: 10579470
• 负责人: Eric Y Chang
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579470
• 关键词: Alkalinization; Anemia; Animal Model; Binding; Biological Markers; Biology; Biomechanics; Blood Vessels; Bone Density; Bone Diseases; Bone Marrow; Bone Tissue; Bone remodeling; Bone structure; Cadaver; Caring; Chemicals; Chronic; Clinic; Clinical; Collagen; Deterioration; Development; Diffusion; Dual-Energy X-Ray Absorptiometry; Effectiveness; Electrodes; Environment; Evaluation; Fracture; Functional disorder; Goals; Grant; Healthcare Systems; Hindlimb; Histology; Hypertension; Imaging Techniques; Immune System Diseases; Infection; Investigation; Knee; Life; Locomotion; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mechanics; Modality; Modeling; Motor Activity; Movement; Neurons; Osteoporosis; Paralysed; Pathogenesis; Pathologic; Pathological fracture; Patients; Physiological; Physiology; Property; Protons; Rattus; Recovery; Reference Standards; Relaxation; Risk; Roentgen Rays; Role; Sampling; Series; Site; Spinal; Spinal cord injury; Spinal cord injury patients; Structure; Sympathetic Nervous System; Techniques; Technology; Testing; Thoracic spinal cord structure; Time; Tissues; Translating; Treatment Effectiveness; United States Department of Veterans Affairs; Use of New Techniques; Venous Engorgements; Vertebral column; Water; X-Ray Computed Tomography; acquired bone marrow failure; behavioral outcome; biomarker panel; biomechanical test; bone; bone health; bone imaging; bone marrow failure syndrome; bone quality; chemical property; clinically relevant; density; designer receptors exclusively activated by designer drugs; effectiveness testing; experience; extracellular; imaging modality; in vivo; insight; interest; magnetic resonance imaging biomarker; mechanical properties; military veteran; molecular scale; morphometry; neuroregulation; novel; osteoporosis with pathological fracture; restoration; skeletal; tool

After traumatic spinal cord injury (SCI), significant deterioration of bone tissue is seen in most patients. This continues throughout life and about 50% of chronic SCI patients will sustain a low-impact or spontaneous fracture at some point, typically occurring around the knee. Traditionally, the pathogenesis of osteoporosis after SCI has been focused on mechanical unloading and its effect on bone quantity, but advances in the field of skeletal biology have revealed the involvement of a much broader array of bone physiology—in particular the critical roles that the structural, physiological, and chemical properties of bone contribute to bone health. Evaluating the multi-scale changes that occur in bone tissue components such as the organic matrix and water, which together occupy approximately 60% of bone by volume, can provide critical information on chronic SCI risks including osteoporotic fracture, as well as the anemia and immune dysfunction associated with the “acquired bone marrow failure syndrome.” Unfortunately, such crucial information on bone structure, vascularity, and chemical properties is all but inaccessible using the standard imaging modalities available in clinics today. Magnetic resonance imaging (MRI), particularly ultrashort echo time (UTE) techniques, continues to gain interest for the investigation of numerous structural and physiological properties of bone. The development and application of quantitative UTE MRI techniques to measure multi-scale features of bone, including macro- and micro-scale structure (UTE), micro-scale vascularity (UTE double echo steady state [UTE-DESS]), and molecular-scale chemical properties (UTE acido-chemical exchange saturation transfer [UTE-acidoCEST]), would represent a revolutionary step forward in the care of SCI patients. The goal of this proposal is to establish a panel of non-invasive MRI biomarkers tailored for bone quality assessment in SCI and test its effectiveness on a novel chronic SCI rat model. In the first Aim, cadaveric knee samples from SCI and healthy donors will be used to optimize a panel of novel, quantitative MRI techniques for fast and accurate volumetric evaluation of bone quality and health. The first hypothesis is that multi-scale bone quality and health measures can be reliably assessed using the new techniques. The second hypothesis is that the new biomarkers will be highly correlated with reference standards, including bone structure, composition, biomechanical properties, vascular density, and pH measures. In the second Aim, a longitudinal rat model with chronic, complete T8 SCI will be used and investigations will focus on validating the new MRI biomarker panel to assess bone recovery after induction of functional locomotion through manipulation of activity level in propriospinal neurons (via Designer Receptors Exclusively Activated by Designer Drugs) with and without sympathetic inhibition. The third hypothesis is that the biomarker panel will be highly correlated with µCT, histology, and behavioral outcomes, and will accurately detect longitudinal changes in bone quality associated with chronic complete thoracic SCI. The fourth hypothesis is that alterations in local sympathetic control of hindlimbs make substantial contributions to bone remodeling and dysfunction, which can be mitigated with sympathetic inhibition. After the successful completion of this grant, we expect to provide an optimized MRI panel that is tailored for multi-scale evaluation of bone in SCI, use an animal model to provide insight into the degree of bone recovery that may be expected with neuromodulation, and be the first to explore the effects of sympathetic nervous system activity in sublesional bone in vivo.

创伤性脊髓损伤（SCI）后，在大多数患者中可以看到骨组织的显著恶化。这 这种情况会持续一生，大约50%的慢性SCI患者会出现低强度骨折或自发性骨折 通常发生在膝盖周围传统上，脊髓损伤后骨质疏松症的发病机制 近年来，国内外学者对机械去负荷及其对骨量的影响的研究较多， 生物学已经揭示了更广泛的骨生理学的参与-特别是关键的 骨的结构、生理和化学特性对骨健康的作用。评价 在骨组织成分中发生的多尺度变化，如有机基质和水， 约占骨体积的60%，可以提供有关慢性SCI风险的关键信息，包括 骨质疏松性骨折，以及贫血和免疫功能障碍与“获得性骨髓 失败综合症”不幸的是，这些关于骨骼结构、血管分布和化学性质的关键信息， 使用目前诊所中可用的标准成像模式几乎无法获得。磁共振 磁共振成像（MRI），特别是超短回波时间（UTE）技术，继续获得研究的兴趣 骨骼的许多结构和生理特性。定量分析技术的发展与应用 UTE MRI技术用于测量骨骼的多尺度特征，包括宏观和微观尺度结构（UTE）， 微尺度血管分布（UTE双回波稳态[UTE-DESS]）和分子尺度化学性质 (UTE酸化学交换饱和转移[UTE-acidoCEST]），将代表革命性的一步 为SCI患者提供护理。这项建议的目标是建立一个小组的非侵入性MRI 为SCI骨质量评估定制的生物标志物，并在新型慢性SCI大鼠上测试其有效性 模型在第一个目标中，来自SCI和健康供体的尸体膝关节样本将用于优化一组 新的定量MRI技术，用于快速准确的骨质和健康体积评估。的 第一个假设是，多尺度骨质量和健康措施可以可靠地评估使用新的 技术.第二个假设是新的生物标志物将与参考标准高度相关， 包括骨结构、组成、生物力学性质、血管密度和pH测量。在 第二个目标，将使用慢性完全T8 SCI的纵向大鼠模型，研究将集中在 验证新的MRI生物标志物面板，以评估功能性运动诱导后的骨恢复， 操纵脊髓本体神经元的活动水平（通过设计者受体专门激活设计者） 有或没有交感神经抑制。第三个假设是，生物标志物小组将高度 与µCT、组织学和行为结果相关，并将准确检测骨的纵向变化 与慢性完全性胸脊髓损伤相关的质量。第四个假设是， 后肢的交感神经控制对骨重建和功能障碍做出了实质性贡献，这可以 可以通过交感神经抑制来缓解。在成功完成这笔赠款后，我们希望提供一个 优化的MRI面板，专为SCI中骨的多尺度评估而设计，使用动物模型提供 深入了解神经调节可能预期的骨恢复程度，并率先探索 交感神经系统活性在病灶下骨中的影响。