Modulating Cellular Bioenergetics to Improve Skeletal Health

项目概要/摘要 我的研究项目的长期目标是全面了解代谢是如何 路径影响骨骼健康。与这一目标相一致，我们的愿景是应用战略， 生物学机制，这导致了新的治疗方法的发展，可以提高生活质量， 骨质疏松患者。 骨质疏松症和骨质减少症是迟发性疾病，在美国影响着惊人的5400万人 除了经济负担外，骨关节炎相关的骨折通常导致多种合并症， 大大缩短了寿命。而增加骨形成的合成代谢药物，如甲状旁腺 . 在 虽然激素（PTH）有助于骨质疏松症的管理，但患者仍然会遇到不良副作用。 因此，有必要继续开发完善的治疗方案。相对于此，目前 该项目旨在利用PTH调节成骨细胞生物能量能力的能力来促进骨形成 通过提供能量脂肪酸底物来满足这种需求。靶向骨细胞中的代谢途径是一种 高度挑衅性的工具，可用于打击各种肌肉骨骼条件，导致 增加的断裂发生率（即，绝经后骨质疏松症和年龄相关性骨质疏松症）。在这 范围，目前的项目旨在探讨间歇性甲状旁腺激素（iPTH）的骨合成代谢作用 通过调节骨骼龛内细胞的脂质代谢。因此，总体假设是 iPTH的骨合成代谢作用可以通过向成骨细胞提供外源性脂肪酸来增强。 这一假设将在两个具体目标中得到检验。第一个目标将利用体内模型系统来确定 是否操纵外源性脂肪酸的可用性影响iPTH诱导的骨形成。的 第二个目标将进一步证明PTH诱导的成骨细胞活性改变依赖于增加的 使用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 预计会产生重大的健康相关影响。具体而言，该项目产生的数据可能会 通过（1）鉴定新的骨合成代谢机制，（2）帮助 优化当前FDA批准的骨合成代谢剂的给药策略和/或功效，以预防 骨关节炎相关骨折，以及（3）导致其他药物治疗的确定 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.