Serotonin as a Regulator of Bone Mass Accrual: Basic and Clinical

该计划项目申请的总体目标是通过确定一种新的调节剂，阐明其作用模式并记录其临床重要性，提高我们对衰老背景下骨重建的遗传和分子控制的理解。这四个项目将研究（1）脑源性5-羟色胺在调节骨形成中的作用及其作用机制（Karsenty）;（2）肠源性5-羟色胺调节成骨细胞增殖和骨形成的分子机制（3）脑源性和肠源性5-羟色胺之间的功能等级以及抑制肠源性5-羟色胺合成的治疗潜力;（4）5-羟色胺参与人类抑郁症和性腺衰竭引起的骨质疏松症（Bilezikian）。这些项目将得到两个基本核心的支持。核心A是整合生物统计支持的管理核心，核心B是提供组织形态学和microCT分析的骨形态学核心。项目的协调工作将由项目主任负责。这将通过项目之间的协同和互补、我们的月度会议、我们与内部（月度）和外部（年度）科学咨询委员会的互动以及核心发挥的支持作用来促进。我们的研究将为骨重建的遗传和分子控制以及骨质疏松症（一种主要的衰老疾病）的发病机制和治疗提供重要和新颖的见解。

The overall goal of this Program Project Application is to improve our understanding of the genetic and molecular control of bone remodeling in the context of aging by identifying a novel regulator, elucidating its modes of action and documenting its clinical importance. The four projects will examine (1) the role of brain-derived serotonin in the regulation of bone formation and its mechanisms of action (Karsenty); (2) the molecular mechanisms whereby gut-derived serotonin regulates osteoblast proliferation and bone formation (Kousteni); (3) the functional hierarchy between brain-derived and gut-derived serotonin as well as the therapeutic potential of inhibiting the synthesis of gut-derived serotonin; (4) the involvement of serotonin in depression-induced and gonadal-failure-induced osteoporosis in humans (Bilezikian). These projects will be supported by two essential cores. Core A is an administrative core integrating a biostatistical support, core B is a Bone Morphometry Core providing histomorphometry and microCT analyses. The coordination of the projects will be performed by the program director. This will be facilitated by the synergy and complementary between the projects, by our monthly meetings, by our interaction with the internal (monthly) and external (yearly) scientific advisory boards and by the supporting roles played by the cores. Together our studies should provide important and novel insights in the genetic and molecular control of bone remodeling as well as in the pathogenesis and treatment of osteoporosis, a major disease of aging.