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