Modulating Cellular Bioenergetics to Improve Skeletal Health

项目摘要/摘要 我的研究计划的长期目标是全面了解新陈代谢是如何 这些途径会影响骨骼健康。与这一目标一致，我们的愿景是应用策略来识别小说 生物机制，这导致了新的治疗方法的开发，可以改善患者的生活质量 骨质疏松症患者。 骨质疏松症和骨质疏松症是晚发性疾病，在美国有5400万人受到影响 除了经济负担外，与骨质疏松相关的骨折往往会导致多种并发症， 大大降低了寿命。而促进骨形成的合成代谢剂，如甲状旁腺 。 在……里面 激素(PTH)有助于治疗骨质疏松症，但患者仍会出现不良反应。 因此，继续开发改进的治疗方案是必要的。相对于这一点，当前 该项目旨在利用甲状旁腺素调节成骨细胞的生物能量能力来促进骨形成 通过提供能量脂肪酸底物来满足这一需求。靶向骨细胞中的代谢途径是一种 极具挑衅性的工具，可用于对抗各种肌肉骨骼疾病，这些疾病导致 骨折发生率增加(即绝经后骨质疏松和年龄相关性骨质疏松)。在这个范围内 目前的项目旨在探索间歇性甲状旁腺激素(IPTH)的骨合成代谢效应。 通过调节骨骼壁龛内细胞的脂类代谢。因此，最重要的假设是 IPTH的骨合成代谢作用可以通过向成骨细胞提供外源脂肪酸来增强。 这一假设将在两个具体目标上得到检验。第一个目标是利用体内模型系统来确定 控制外源性脂肪酸的供应是否影响iPTH诱导的骨形成。这个 第二个目标将进一步证明，甲状旁腺素诱导的成骨细胞活性的改变依赖于 使用一种新的体外方法通过脂肪酸氧化生产三磷酸腺苷(ATP)。这个项目是 预计将对健康产生重大影响。具体地说，从该项目生成的数据可能会 通过(1)确定一种新的骨合成代谢机制，(2)辅助 FDA批准的当前骨合成代谢药物的给药策略和/或疗效的优化，以防止 与骨质疏松相关的骨折，以及(3)导致其他药物疗法的确定 利用类似的机制，所有这些都与改善肌肉骨骼健康直接相关。

PROJECT SUMMARY/ ABSTRACT The long-term goal of my research program is to develop a comprehensive understanding of how metabolic pathways impact bone health. Consistent with this goal, our vision is to apply strategies to identify novel biological mechanisms, which lead to the development of new treatments that can improve the quality of life for patients with bone fragility. Osteoporosis and osteopenia are late-onset diseases affecting a staggering 54 million people in the U.S addition to the financial burden, osteoporosis-related fractures often lead to multiple comorbidities which significantly reduce longevity. While anabolic agents that increase bone formation, such as parathyroid . In hormone (PTH), have aided in the management of osteoporosis, patients still experience adverse side-effects. Therefore, continued development of refined therapeutic options is necessary. Relative to this, the current project aims to harness PTH’s ability to modulate osteoblast bioenergetic capacity to promote bone formation by supplying energy fatty acid substrates to meet this demand. Targeting metabolic pathways in bone cells is a highly provocative tool that can be applied to combat various musculoskeletal conditions which lead to increased fracture incidence (i.e., post-menopausal osteoporosis and age-related osteoporosis). Within this scope, the current project aims to explore the osteo-anabolic effects of intermittent parathyroid hormone (iPTH) via modulation of lipid metabolism on cells within the skeletal niche. Therefore, the overarching hypothesis is that the osteoanabolic actions of iPTH can be enhanced by supplying osteoblasts with exogenous fatty acids. This hypothesis will be tested in two specific aims. The first aim will utilize in vivo model systems to determine whether manipulation in the availability of exogenous fatty acids influences iPTH-induced bone formation. The second aim will further demonstrate that PTH-induced alterations in osteoblast activity rely on increased adenosine triphosphate (ATP) production via fatty acid oxidation using a novel in vitro method. This project is expected to have substantial health-related influence. Specifically, data generated from this project are likely to translate directly to improve clinical outcomes by (1) identifying a novel bone anabolic mechanism, (2) aid in the optimization of dosing strategy and/or efficacy of a current FDA-approved bone anabolic agent to prevent osteoporotic-related fracture, as well as (3) lead to the identification of other pharmaceutical therapies exploiting similar mechanisms, all of which are directly related to improving musculoskeletal health.