Interdisciplinary Study of Marrow Adiposity, Mineral Metabolism & Energy Balance

骨髓肥胖、矿物质代谢的跨学科研究

• 批准号: 8183483
• 负责人: MARK C HOROWITZ
• 金额: $ 127.05万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8183483
• 关键词: 2,4-thiazolidinedione; Abdomen; Address; Adipocytes; Adipose tissue; Affect; Age; Age-Related Bone Loss; Aging; Animal Model; Animals; Anorexia; Anorexia Nervosa; Aplastic Anemia; Architecture; Back; Biochemical; Body Weight; Bone Marrow; Bone Marrow Transplantation; Bone remodeling; Brown Fat; Caloric Restriction; Cell Separation; Cell surface; Cells; Cellular biology; Characteristics; Chronic; Clinical; Clinical Research; Contracts; Cues; Data; Development; Diabetes Mellitus; Diet; Disease; Drug usage; Dual-Energy X-Ray Absorptiometry; Energy Intake; Energy Metabolism; Fatty acid glycerol esters; Filler; Finite Element Analysis; Flow Cytometry; Fracture; Functional disorder; Gene Expression; Genes; Genetic; Glucocorticoids; Growth; Hematopoiesis; Hematopoietic; Homeostasis; Hormonal; Hormones; Human; Imaging Techniques; In Vitro; Inbred C3H Mice; Individual; Insulin Resistance; Interdisciplinary Study; Knowledge; Laboratories; Leptin; Link; Lipolysis; Magnetic Resonance Imaging; Maintenance; Marrow; Measures; Metabolic; Metabolic Diseases; Metabolism; Minerals; Modeling; Molecular Genetics; Molecular Profiling; Monoclonal Antibody R24; Multiple Myeloma; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nutrient; Nutritional; Nutritional status; Obesity; Oryctolagus cuniculus; Osteogenesis; Patients; Peripheral; Phenotype; Physiological; Play; Positron-Emission Tomography; Principal Investigator; Proteomics; Relative (related person); Reporting; Research Personnel; Resolution; Rest; Risk; Role; Signal Transduction; Site; Source; Structure; Sum; Surface; Techniques; Testing; Thermogenesis; Thiazolidinediones; Time; Woman; adipokines; adiponectin; bone; bone loss; bone mass; bone strength; bone turnover; clinically relevant; data integration; energy balance; glucose uptake; in vivo; innovation; lipid biosynthesis; longitudinal design; metabolomics; novel; novel therapeutic intervention; progenitor; response; skeletal; skeletal disorder; substantia spongiosa; translational approach; virtual

DESCRIPTION (provided by applicant): This proposal will systematically address a fundamental and clinically relevant question: What is the function of bone marrow adipose tissue (MAT)? Adipocytes were identified in the marrow more than a century ago, but questions about their relevance to energy homeostasis have only recently surfaced. These questions coincide with emerging data indicating that adipose depots at different sites have distinct physiologic functions and play critical roles in the pathophysiology of both metabolic and skeletal disorders. In the current project we are focused on the structure and function of bone marrow adipocytes, a unique and understudied depot that we hypothesize is associated with growth, nutritional status, and skeletal remodeling. With pilot support from R24 NIDDK 84970, we developed an integrated and multidisciplinary research team, explored new animal and human models, applied new techniques in metabolomics, developed a virtual laboratory for investigator integration, and used innovative imaging techniques for both MAT and bone micro- architecture. We also demonstrated that: 1) marrow adipocytes have unique cell surface markers that distinguish them from adipocytes in other depots; 2) MAT is dynamic, with the capacity to expand or contract in response to developmental and nutritional cues such as calorie restriction; 3) adiponectin expression and basal lipolytic rates are higher in marrow adipocytes than in adipocytes from other depots; 4) MAT is closely linked to bone remodeling and bone mass in humans. Most importantly, in a translational model of chronic calorie restriction, anorexia nervosa (AN), we showed that MAT was markedly increased compared to young age-matched controls and was inversely related to bone mass and the size of other fat depots. Therefore, we propose specific aims which will test the central hypothesis that MAT is an important modulator of skeletal remodeling and is fully integrated in energy homeostasis. The three aims are:1) Determine the function of MAT relative to bone remodeling; 2) Assess the metabolic status of MAT and contrast this with other adipose depots; 3) Define the adipocyte progenitor(AP) and its differentiation in bone marrow, and identify the genetic, molecular, biochemical and hormonal profile of MAT. PUBLIC HEALTH RELEVANCE: Excess MAT is associated with greater fracture risk and low bone mass. Understanding the function of marrow adipocytes and their relationship to skeletal remodeling will help identify patients at risk for fractures in disorders like anorexia nervosa, diabetes mellitus, multiple myeloma and age-related osteoporosis. Data generated from this project also holds promise for new therapeutic approaches to preserve bone mass.

描述（由申请人提供）：该提案将系统地解决一个基本的和临床相关的问题：骨髓脂肪组织（MAT）的功能是什么？早在世纪以前，人们就在骨髓中发现了脂肪细胞，但关于脂肪细胞与能量平衡的关系的问题直到最近才浮出水面。这些问题与新出现的数据相吻合，这些数据表明，不同部位的脂肪库具有不同的生理功能，并在代谢和骨骼疾病的病理生理学中发挥关键作用。在目前的项目中，我们专注于骨髓脂肪细胞的结构和功能，这是一个独特的和未充分研究的仓库，我们假设与生长，营养状况和骨骼重塑有关。在R24 NIDDK 84970的试点支持下，我们建立了一个综合的多学科研究团队，探索了新的动物和人类模型，应用了代谢组学的新技术，开发了一个虚拟实验室用于研究者整合，并使用了MAT和骨微结构的创新成像技术。我们还证明了：1）骨髓脂肪细胞具有独特的细胞表面标志物，其将它们与其他贮库中的脂肪细胞区分开; 2）MAT是动态的，具有响应于发育和营养线索（例如卡路里限制）而扩张或收缩的能力; 3)骨髓脂肪细胞中脂联素的表达和基础脂解率高于其他脂肪细胞; 4）MAT与人类骨重建和骨量密切相关。最重要的是，在慢性热量限制的转化模型中，神经性厌食症（AN），我们发现MAT与年轻年龄匹配的对照组相比显着增加，并且与骨量和其他脂肪库的大小呈负相关。因此，我们提出了具体的目标，这将测试中心的假设，MAT是一个重要的调制器的骨骼重塑，并完全整合在能量稳态。这三个目标是：1）确定MAT相对于骨重建的功能; 2）评估MAT的代谢状态，并将其与其他脂肪库进行对比; 3）定义脂肪祖细胞（AP）及其在骨髓中的分化，并确定MAT的遗传，分子，生化和激素谱。 公共卫生相关性：过量MAT与更大的骨折风险和低骨量相关。了解骨髓脂肪细胞的功能及其与骨骼重塑的关系将有助于识别神经性厌食症、糖尿病、多发性骨髓瘤和年龄相关性骨质疏松症等疾病中骨折风险的患者。从这个项目产生的数据也有希望为新的治疗方法，以保持骨量。