Determining the Biological Mechanisms of Pathological Cortical Porosity

确定病理性皮质孔隙的生物学机制

• 批准号: 10251896
• 负责人: GALATEIA J KAZAKIA
• 金额: $ 27.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251896
• 关键词: Age; Aging; Ancillary Study; Automobile Driving; Biological; Biomechanics; Blood Vessels; Clinical; Cohort Studies; Data; Development; Diabetes Mellitus; Drug Targeting; Fatty acid glycerol esters; Fracture; Funding; Future; Goals; Growth; Health; Image; Knowledge; Longitudinal Studies; Magnetic Resonance Imaging; Maps; Marrow; Microvascular Dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Nutrient Canals; Obesity; Osteon; Parents; Pathologic; Patients; Porosity; Prevalence; Prevention; Process; Protocols documentation; Spatial Distribution; Techniques; Therapeutic Studies; Time; Vascular System; Visit; Visualization; Work; age related; base; biological systems; bone fragility; bone imaging; bone strength; cellular targeting; cohort; cortical bone; diabetes control; drug development; follow-up; fracture risk; healthy aging; imaging study; innovation; lipid metabolism; prevent; research clinical testing; skeletal

SUMMARY Cortical bone porosity is a major determinant of bone strength. In fact, age-related increases in cortical porosity account for more than 75% of the concomitant reduction in cortical bone strength. Further, our group and others have found that increased cortical porosity is associated with elevated fracture prevalence in patients with type 2 diabetes (T2D). Despite the biomechanical importance of cortical porosity, the biological drivers of cortical pore expansion are unknown. Filling this knowledge gap will elucidate appropriate cellular targets for drug development to prevent or reverse pathological pore development and the associated skeletal fragility. The biological systems influencing pore expansion can be revealed by visualizing the content of cortical pore space. Our team has developed innovative magnetic resonance imaging (MRI)-based acquisition and processing techniques to visualize vasculature and fat within cortical pores, both of which have been implicated in pore expansion. We propose to detect new pore space formed over the course of a longitudinal skeletal imaging study, identify the content of that new pore space, and in this way determine the biological system(s) driving development of the new pore space. The proposed parent study is an ongoing longitudinal study of cortical pore development in the context of T2D. The aim of the parent study is to quantify longitudinal changes in cortical porosity in patients with T2D and in healthy controls. Further, the parent study applies our MRI-based pore content visualization technique to the baseline time-point of the study (only) to compare pore content between T2D and healthy cohorts and to evaluate associations between pore content and clinical evaluations of vascular health and fat metabolism. The parent study does not include MRI at the follow-up visit, and therefore will not be able to answer the question: In T2D and healthy controls, is the vascular system, the marrow fat, or both responsible for increased cortical porosity over time? In this ancillary study, we will add the MRI-based pore content visualization to the follow-up visit of the parent study. We will directly image the content of pores that develop and/or expand over the 2-year follow-up period, and in this way reveal the mechanisms associated with pore space expansion. By leveraging the parent study we capture a well- characterized cohort, with all necessary clinical and imaging data already acquired, with the exception of the follow-up MRI. This application meets the time sensitivity requirement of the funding announcement: in order to efficiently leverage the established parent study cohort, the pore content visualization technique must be added by early 2020. This work will identify the biological systems driving increased porosity associated with aging and T2D, as well as potential drug targets for the prevention or reversal of age- and T2D-related pathological porosity and bone fragility, laying the groundwork for future therapeutic studies. With the general populating aging and the prevalence of T2D rising, this study has the potential for immense clinical impact.

总结 皮质骨孔隙率是骨强度的主要决定因素。事实上，与年龄相关的皮质孔隙度增加 占皮质骨强度降低的75%以上。此外，我们的团队和 其他人发现皮质孔隙度的增加与患者骨折发生率的升高有关 2型糖尿病（T2 D）尽管皮质多孔性的生物力学重要性， 皮质孔扩张未知。填补这一知识空白将阐明适当的细胞靶点， 预防或逆转病理性毛孔发育和相关骨骼脆弱性的药物开发。 通过观察皮层孔的含量，可以揭示影响孔扩张的生物系统 空间我们的团队开发了创新的基于磁共振成像（MRI）的采集和 处理技术，以可视化皮质孔内的脉管系统和脂肪，这两者都已被 与毛孔扩张有关。我们建议检测新的孔隙空间形成的过程中，纵向 骨骼成像研究，确定新孔隙的内容物，并以这种方式确定生物 驱动新孔隙空间发展的系统。拟议的母研究是一项正在进行的纵向研究， T2 D背景下皮质孔发育的研究。母研究的目的是量化纵向 2型糖尿病患者和健康对照者的皮质孔隙度变化。此外，家长研究适用于我们的 基于MRI的孔隙含量可视化技术与研究基线时间点（仅）比较孔隙 T2 D和健康队列之间的孔隙含量，并评估孔隙含量和临床 血管健康和脂肪代谢的评估。母研究不包括随访访视时的MRI， 因此无法回答这个问题：在T2 D和健康对照中，血管系统， 骨髓脂肪，或两者都负责增加皮质孔隙随着时间的推移？在本辅助研究中，我们将添加 基于MRI的孔隙含量可视化至母研究的随访访视。我们将直接成像 在2年随访期内发展和/或扩张的孔隙的含量，并以这种方式揭示 与孔隙空间膨胀相关的机制。通过利用母公司研究，我们获得了一个很好的- 已获得所有必要的临床和成像数据，但 后续MRI。本申请符合资助公告的时间敏感性要求： 有效地利用已建立的母研究队列，孔隙含量可视化技术必须 到2020年初增加。这项工作将确定生物系统驱动增加孔隙度与 衰老和T2 D，以及用于预防或逆转年龄和T2 D相关疾病的潜在药物靶点 病理性多孔性和骨脆性，为未来的治疗研究奠定基础。与一般 随着人口老龄化和T2 D患病率的上升，这项研究有可能产生巨大的临床影响。