Modulating Cellular Bioenergetics to Improve Skeletal Health

调节细胞生物能量以改善骨骼健康

• 批准号: 10527457
• 负责人: Elizabeth Rendina-Ruedy
• 金额: $ 22.03万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527457
• 关键词: Address; Adenosine Triphosphate; Adipose tissue; Adult; Adverse event; Affect; Age; Age-Related Osteoporosis; Anabolic Agents; Area; Bioenergetics; Biological; Biological Assay; Biological Models; Biology; Bolus Infusion; Bone Density; Bone Marrow; Cells; Clinical; Data; Development; Dietary Fatty Acid; Dose; Effectiveness; Energy Supply; Experimental Models; FDA approved; Fatty Acids; Femur; Financial Hardship; Forteo; Fracture; Gene Expression Profile; Goals; Health; Histology; Hormones; In Vitro; Incidence; Kinetics; Late-Onset Disorder; Lead; Lipids; Longevity; Mass Spectrum Analysis; Measurement; Metabolic Pathway; Metabolism; Methodology; Methods; Mitochondria; Monitor; Mus; Musculoskeletal; Oleic Acids; Osteoblasts; Osteogenesis; Osteopenia; Osteoporosis; Osteoporotic; Outcome; Oxygen Consumption; PTH gene; Parathyroid gland; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Population; Populations at Risk; Postmenopausal Osteoporosis; Preparation; Price; Production; Proteins; Public Health; Quality of life; Research; Respiration; Sample Size; Sampling; Stimulus; Stromal Cells; Testing; Therapeutic; Transfection; Translating; Vision; Work; Workload; X-Ray Computed Tomography; base; biomechanical test; bone; bone cell; bone fragility; bone health; bone mass; bone metabolism; cell type; combat; comorbidity; cost; efficacy testing; experimental study; fatty acid metabolism; fatty acid oxidation; fatty acid supplementation; fracture risk; high reward; hormone therapy; improved; in vivo; in vivo Model; lipid metabolism; luminescence; novel; nutrition; osteoporosis with pathological fracture; oxidation; prevent; primary outcome; programs; response; secondary outcome; side effect; skeletal; spine bone structure; tool

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.

项目摘要/摘要 我的研究计划的长期目标是对新陈代谢的方式进行全面了解 途径影响骨骼健康。与这个目标一致，我们的愿景是采用策略来识别新颖 生物机制，导致开发新疗法，可以改善生活质量 患有骨骼脆弱的患者。 骨质疏松症和骨质减少症是影响美国5400万人惊人的晚期疾病 除了经济燃烧，与骨质疏松相关的骨折通常会导致多种合并症 而合成代谢剂会增加骨形成，例如甲状旁腺 。 在 马酮（PTH）有助于治疗骨质疏松症，患者仍然遭受不良副作用。 因此，有必要继续开发精制治疗方案。相对于此，电流 项目旨在利用PTH调节成骨细胞生物能力以促进骨形成的能力 通过提供能量脂肪酸底物以满足这一需求。靶向骨细胞中的代谢途径是 高度挑衅的工具，可用于对抗各种肌肉骨骼条件，这导致 骨折发生率增加（即，绝经后骨质疏松症和与年龄有关的骨质疏松症）。在此 范围，目前的项目旨在探索间歇性甲状旁腺激素（IPTH）的骨抗代谢作用 通过调节骨骼利基内细胞上的脂质代谢。因此，总体假设是 可以通过用外源脂肪酸供应成骨细胞来增强IPTH的骨动物代谢作用。 该假设将以两个具体的目的进行检验。第一个目标将利用体内模型系统来确定 外源脂肪酸的可用性中的操纵是否会影响IPTH诱导的骨形成。这 第二个目标将进一步证明，PTH引起的成骨细胞活动的改变依赖于增加 三磷酸腺苷（ATP）使用一种新型体外方法通过脂肪酸氧化产生。这个项目是 预计将具有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）识别新型骨合成代谢机制，直接转化以改善临床结果，（2）帮助 优化当前FDA批准的骨合代剂的剂量策略和/或效率以防止 与骨质疏松相关的裂缝以及（3）导致其他药物疗法的鉴定 利用类似的机制，所有这些机制都与改善肌肉骨骼健康直接相关。