Mesenchymal and Neural Regulation of Metabolic Networks

全身新陈代谢受包括脂肪组织在内的多个器官系统的整合调节， 骨骼和骨髓。这些组织调节的不平衡会导致慢性疾病，如 肥胖和骨质疏松症。脂肪细胞和骨祖细胞共享共同的间充质前体，并且 将这两种高度流行的疾病联系起来。间充质祖细胞在衰老过程中也受到严格的调控， 营养压力和快速的温度变化。越来越多的人意识到，同情心紧张 无论是在健康状态下还是在疾病状态下，系统在这种代谢调节中都发挥着独特的作用。我们的整体 计划的目标是定义整合大脑、骨骼和脂肪的特定分子和信号通路 组织在新陈代谢网络中的调节。这个Cobre项目，由Lucy Liw博士和Clifford Rosen博士领导， 汇集了四个测试脂肪细胞和骨骼代谢功能互补方面的项目，以及 它们通过中枢神经系统的输入进行调节。项目1(A.Brown)将研究BMP信号在 棕色脂肪生成和生热作用，并将优化人诱导性多能干细胞来源的棕色的生热能力 通过修改BMP信号调节脂肪细胞。这个项目对肥胖有很高的翻译意义。 以及与之相关的共病。项目2(M·里根)阐述了骨髓的起源和功能 脂肪组织，一种独特的储存库，可增强骨质疏松和肥胖，并可能有助于骨骼 脆弱。这个项目将检验新的假设，即骨细胞衍生的硬化素促进骨髓 通过抑制Wnt信号的脂肪生成，并将利用生物工程方法和小鼠模型 改变了骨骼生理学。项目3(C.Duarte)是一个翻译项目，涉及以下方面的后果 非典型抗精神病药物对骨折风险的影响。非典型抗精神病药物如利培酮(RIS)高度 治疗精神和行为症状的处方，并有包括骨质流失在内的副作用，增加 骨折风险和体重增加。该项目将研究疗养院居民，包括RIS的普遍用户 以及β阻滞剂，这两种药物在动物研究中单独显示出对骨质丢失的保护作用。这个项目将决定 与单独使用RIS相比，RIS和β阻滞剂联合使用可降低骨折风险。项目4(K. Motyl)是对Project 3的补充，并使用老鼠模型来测试RIS所作用的新假设 中枢神经系统直接或通过激活棕色脂肪组织来靶向骨质丢失。这个项目 对大脑中支配骨骼的区域的RIS提出了新的分析，并测试了RIS- 棕色脂肪组织的诱导激活可以反过来调节骨丢失。这些项目将由 强调科学协作和持续发展的行政和专业发展核心 专业发展和三个科学核心：(一)蛋白质组学和脂质组学核心(C.Varie)，(二) 组织病理学和组织形态计量学核心(V.Lindner)，以及(Iii) 新陈代谢网络的间质和神经调节。

Whole body metabolism is regulated by the integration of multiple organ systems, including adipose tissue, the skeleton, and bone marrow. Imbalance in the regulation of these tissues leads to chronic disorders such as obesity and osteoporosis. Adipocytes and osteoprogenitor cells share a common mesenchymal precursor, and link these two highly prevalent diseases. Mesenchymal progenitors are also tightly regulated during aging, nutritional stress, and rapid temperature shifts. There is growing appreciation that the sympathetic nervous system plays a unique role in this metabolic regulation, both in health and in disease states. Our overall program goal is to define specific molecular and signaling pathways that integrate the brain, bone, and adipose tissue in regulation of metabolic networks. This COBRE program, led by Drs. Lucy Liaw and Clifford Rosen, brings together four projects that test complementary aspects of adipocyte and skeletal metabolic function, and their regulation by central nervous system input. Project 1 (A. Brown) will study the role of BMP signaling in brown adipogenesis and thermogenesis, and will optimize thermogenic capacity in human iPS-derived brown adipocytes by modifying BMP signaling. This project has high translational significance in relation to obesity and its related co-morbidities. Project 2 (M. Reagan) addresses the origin and function of bone marrow adipose tissue, a unique depot that is enhanced in osteoporosis and obesity, and may contribute to skeletal fragility. This project will test the novel hypothesis that osteocyte-derived sclerostin promotes marrow adipogenesis via inhibition of Wnt signaling, and will utilize bioengineering approaches and mouse models of altered bone physiology. Project 3 (C. Duarte) is a translational project addressing the consequences of atypical antipsychotics on bone fracture risk. Atypical antipsychotics such as risperidone (RIS) are highly prescribed for psychiatric and behavioral symptoms, and have side effects that include bone loss, increased fracture risk, and weight gain. This project will study nursing home residents, including prevalent users of RIS and β-blockers, which alone show a protective effect on bone loss in animal studies. This project will determine if the combination of RIS and β-blockers reduce the risk of fracture compared to RIS alone. Project 4 (K. Motyl) is complementary to Project 3, and uses mouse models to test the novel hypothesis that RIS acts on the central nervous system to target bone loss directly or via activation of brown adipose tissue. This project proposes novel analyses of RIS in brain regions that innervate bone, and also tests the hypothesis that RIS- induced activation of brown adipose tissue can, in turn, mediate bone loss. These projects will be supported by an Administrative and Professional Development Core that emphasizes scientific collaboration and continued professional development, and three scientific cores: (i) Proteomics and Lipidomics Core (C. Vary), (ii) Histopathology and Histomorphometry Core (V. Lindner), and (iii) Physiology Core for the Mesenchymal and Neural Regulation of Metabolic Networks COBRE (C. Rosen).