Interdisciplinary study of marrow adiposity, mineral metabolism,and energy balanc

描述(申请人提供)：长期以来，骨髓肥胖症一直被认为是骨髓微环境的一个组成部分，尽管它的功能、与矿物质代谢的相关性以及与能量平衡的关系直到最近才被忽视。脂肪细胞来源于一种常见的间充质干细胞，该干细胞还可分化为成骨细胞(骨)、软骨细胞(软骨)、肌细胞(肌肉)或基质(造血支持)细胞。尽管间充质干细胞的分配决定了祖细胞只进入一个谱系，但越来越多的证据表明，骨髓脂肪细胞群体是动态的，有能力在动物整个生命周期内响应遗传、发育和生理信号而扩张或收缩。此外，与代谢改变相关的疾病，如衰老、糖尿病、糖皮质激素治疗和神经性厌食症，都以骨髓脂肪细胞异常堆积为特征。因此，骨髓脂肪生成一直被认为是中性的，或者是对因骨小梁丢失而腾出的骨髓空间进行填充。然而，目前还没有数据来定义骨髓脂肪在正常发育过程中的生理作用或与能量状态相关的生理作用。这项建议的主要目标是全面规划一种跨学科的方法，以确定骨髓脂肪相对于能量平衡和矿物质代谢的功能。为了实现这一目标，四位长期对骨骼和脂肪细胞生物学感兴趣的受人尊敬的研究人员将共同努力，制定一项确定骨髓肥胖症的生理和病理方面的战略。这笔为期一年的“种子”拨款将使这些科学家能够利用小鼠模型、代谢组学、结构成像、分子生物学和临床研究来协同他们的研究努力，以共同确定实验范式，以了解骨髓肥胖症的代谢悖论。我们预计，在为期一年的项目结束时，研究人员将非常适合确定骨髓脂肪形成的过程及其与矿物质代谢的关系。 公共卫生相关性：这项提议的长期目标是协同骨和脂肪细胞生物学领域的四位专家的努力。该小组将计划进行一系列研究，以帮助确定骨髓中脂肪组织的功能及其与糖尿病和神经性厌食症等代谢紊乱的关系。

DESCRIPTION (provided by applicant): Marrow adiposity has long been identified as a component of the bone marrow micro-environment, although its function, relevance to mineral metabolism and relationship to energy homeostasis has been ignored until recently. Adipocytes originate from a common mesenchymal stem cell that also gives rise to osteoblasts (bone), chondrocytes (cartilage), myocytes (muscle), or stromal (hematopoietic support) cells. Although mesenchymal stem cell allocation dictates that progenitor cells enter only one lineage, there is emerging evidence that marrow adipocyte populations are dynamic, with the capacity to expand or contract in response to genetic, developmental and physiological cues across the lifespan of the animal. In addition, conditions associated with altered metabolism such as aging, diabetes mellitus, glucocorticoid therapy, and anorexia nervosa are all characterized by abnormal accumulation of marrow adipocytes. As such, marrow adipogenesis has been considered neutral, or 'filler' for the marrow space vacated by loss of trabecular bone. However, at the present time, no data exist to define the physiologic role of marrow fat during normal development or relative to energy status. The primary goal of this proposal is to comprehensively plan an inter-disoiplinary approach to define the function of marrow fat relative to energy balance and mineral metabolism. In order to accomplish this, four respected investigators with long-standing interests in skeletal and adipocyte biology will work together to map a strategy for defining physiologic and pathologic aspects of marrow adiposity. This one year "Seeding" grant will enable these scientists to synergize their research efforts using mouse models, metabolomics, structural imaging, molecular biology, and clinical studies for the common purpose of defining experimental paradigms to understand the metabolic paradox of marrow adiposity. We anticipate that at the end of the one-year project the investigators will be well suited to define the process of marrow adipogenesis and its relationship to mineral metabolism. PUBLIC HEALTH RELEVANCE: The long term goal of this proposal is to synergize the efforts of four experts in the fields of bone and adipocyte biology. This group will plan a series of studies that will help define the function of adipose tissue in the bone marrow and its relationship to metabolic disorders such as diabetes mellitus and anorexia nervosa.