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

创伤性脊髓损伤(SCI)后，大多数患者的骨组织明显恶化。这 持续终生，约50%的慢性脊髓损伤患者将持续低冲击性或自发性骨折 在某种程度上，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 主要集中在机械卸载及其对骨量的影响，但在骨骼领域取得了进展 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 骨骼的结构、生理和化学性质对骨骼健康的作用。评估 发生在骨组织成分中的多尺度变化，如有机基质和水，它们一起 按体积计算约占60%的骨骼，可以提供有关慢性脊髓损伤风险的关键信息，包括 骨质疏松性骨折，以及与“获得性骨髓”相关的贫血和免疫功能障碍 失败综合症。“不幸的是，这些关于骨骼结构、血管和化学性质的关键信息 几乎无法使用目前临床上可用的标准成像方式。磁共振 成像(MRI)，特别是超短回波时间(UTE)技术，继续获得对调查的兴趣 骨骼的许多结构和生理特性。数量化技术的发展与应用 UTE MRI技术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(UTE双回波稳态[UTE-DESS])和分子尺度的化学性质 (UTE酸化学交换饱和转移[UTE-ACIDOCEST])，将代表着革命性的一步 在脊髓损伤患者的护理方面向前迈进。这项提议的目标是建立一个非侵入性核磁共振小组 用于脊髓损伤骨质量评估的生物标志物及其对新的慢性脊髓损伤大鼠的疗效 模特。在第一个目标中，来自脊髓损伤和健康捐赠者的身体膝盖样本将被用来优化一组 新的定量核磁共振技术，用于快速准确地进行骨骼质量和健康的体积评估。这个 第一个假设是，多尺度的骨骼质量和健康测量可以使用新的 技巧。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、成分、生物力学特性、血管密度和pH值测量。在 第二个目标，将使用一种慢性、完全性T8脊髓损伤的纵向大鼠模型，研究将集中在 新的MRI生物标记物面板用于评估功能性运动诱导后的骨恢复 操纵固有脊髓神经元的活动水平(通过设计者独有地激活的设计者受体 药物)带有和不带有交感神经抑制。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，并将准确检测骨骼的纵向变化 与慢性完全性胸部脊髓损伤相关的质量。第四个假设是局部的改变 后肢的交感神经控制对骨骼重塑和功能障碍有重大贡献，这可能 通过交感抑制得到缓解。在成功完成这笔赠款后，我们预计将提供 优化的MRI面板是为SCI中骨骼的多尺度评估量身定做的，使用动物模型提供 洞察神经调节可能带来的骨骼恢复程度，并率先探索 在体骨下层交感神经系统活动的影响。

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.