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

本项目申请的总体目标是通过识别一种新的调节因子，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塑的遗传和分子控制的理解。这四个项目将研究(1)脑源性血清素在骨形成调控中的作用及其作用机制（Karsenty）；(2)肠源性血清素调节成骨细胞增殖和骨形成的分子机制（Kousteni）；(3)脑源性血清素和肠源性血清素之间的功能层次，以及抑制肠源性血清素合成的治疗潜力；(4)血清素在人类抑郁诱导和性腺功能衰竭诱导的骨质疏松症中的作用（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行政核心，核心B是提供组织形态测量和微ct分析的骨形态测量核心。项目协调工作将由项目主管负责。这将通过项目之间的协同和互补，通过我们的月度会议，通过我们与内部（月度）和外部（年度）科学顾问委员会的互动以及核心所发挥的支持作用来促进。总之，我们的研究应该为骨重塑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.