Modulating Cellular Bioenergetics to Improve Skeletal Health

调节细胞生物能量以改善骨骼健康

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要我的研究计划的长期目标是全面了解新陈代谢如何进行与这一目标一致，我们的愿景是应用策略来识别新的。生物机制，这导致了可以改善生活质量的新疗法的开发骨质脆弱的患者。骨质疏松症和骨质减少症是晚发性疾病，影响着美国多达 5400 万人。除了经济负担外，骨质疏松症相关的骨折通常会导致多种合并症，显着缩短寿命，而促进骨形成的合成代谢药物，例如甲状旁腺。。在激素（PTH）有助于骨质疏松症的治疗，但患者仍然会遇到不良副作用。因此，相对于此，当前的治疗选择的持续开发是必要的。该项目旨在利用 PTH 调节成骨细胞生物能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是针对骨细胞的代谢途径。高度挑衅性的工具，可用于对抗各种肌肉骨骼疾病，这些疾病会导致骨折发生率增加（即绝经后骨质疏松症和年龄相关性骨质疏松症）。目前的项目旨在探索间歇性甲状旁腺激素 (iPTH) 的骨合成代谢作用通过调节骨骼生态位内细胞的脂质代谢因此，总体假设是。向成骨细胞提供外源脂肪酸可以增强 iPTH 的骨合成代谢作用。该假设将在两个具体目标中进行测试，第一个目标将利用体内模型系统来确定。外源脂肪酸的利用是否会影响 iPTH 诱导的骨形成。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使用新型体外方法通过脂肪酸氧化生产三磷酸腺苷（ATP）。具体来说，该项目生成的数据可能会产生重大的健康相关影响。通过以下方式直接转化为改善临床结果：(1) 确定一种新的骨合成代谢机制，(2) 帮助优化目前 FDA 批准的骨合成代谢剂的剂量策略和/或功效，以预防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。