Mesenchymal and Neural Regulation of Metabolic Networks

代谢网络的间充质和神经调节

• 批准号: 10246808
• 负责人: Lucy Liaw
• 金额: $ 227.57万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246808
• 关键词: Acceleration; Address; Adipocytes; Adipose tissue; Adrenergic beta-Agonists; Affect; Aging; Anatomy; Animals; Antipsychotic Agents; Area; Automobile Driving; BMP7 gene; Behavioral Symptoms; Biochemical Pathway; Biology; Biomedical Engineering; Bone Marrow; Bone Morphogenetic Proteins; Bone Tissue; Brain; Brain region; Brown Fat; Cell Communication; Cells; Cellular biology; Centers of Research Excellence; Chronic Disease; Clinical Research; Collaborations; Core Facility; Country; Data; Development; Disease; Economic Burden; Energy Metabolism; Ensure; Equipment; Experimental Models; Fatty acid glycerol esters; Fracture; Goals; Health; Healthcare Systems; Histopathology; Human; Investigation; Investments; Lead; Leadership; Leukocytes; Link; Location; Maine; Marrow; Mediating; Medical center; Mentorship; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Metabolic Bone Diseases; Metabolic Diseases; Metabolism; Methodology; Molecular; Nervous system structure; Neuraxis; Neurons; Nursing Homes; Nutritional; Obesity; Osteocytes; Osteoporosis; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Pilot Projects; Play; Prevention program; Proteomics; Regulation; Research Institute; Research Methodology; Research Personnel; Risperidone; Role; Signal Pathway; Signal Transduction; Signaling Protein; Skeleton; Stress; Sympathetic Nervous System; Technology; Temperature; Testing; Thermogenesis; Tissues; Translational Research; United States; WNT Signaling Pathway; Weight Gain; Work; adipocyte differentiation; atypical antipsychotic; base; body system; bone; bone loss; bone metabolism; brain tissue; career; circadian; cold temperature; comorbidity; embryonic stem cell; energy balance; fatty acid oxidation; fracture risk; human disease; human population study; human study; in vivo; induced pluripotent stem cell; innovation; insight; lipid biosynthesis; lipidomics; metabolic phenotype; mouse model; neuroregulation; neurotransmission; novel; obesity treatment; osteoprogenitor cell; programs; protective effect; psychiatric symptom; side effect; skeletal; stem cells; success; treatment program

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).

全身代谢受多器官系统的整合，包括脂肪组织， 骨骼和骨髓。这些组织调节中的不平衡导致慢性疾病，例如 肥胖和骨质疏松症。脂肪细胞和骨基源细胞具有共同的间充质前体，并且 链接这两种高度普遍的疾病。间充质祖细胞在衰老期间也受到严格调节 营养应激和快速温度转移。越来越感谢同情的紧张 系统在健康和疾病状态中在这种代谢调节中起着独特的作用。我们的整体 程序目标是定义整合大脑，骨骼和脂肪的特定分子和信号通路 组织调节代谢网络的组织。该毛线计划由Drs领导。露西·利亚（Lucy Liaw）和克利福德·罗森（Clifford Rosen）， 汇集了四个测试脂肪细胞和骨骼代谢功能的完工方面的项目，以及 他们对中枢神经系统输入的调节。项目1（A. Brown）将研究BMP信号在 棕色的脂肪形成和热生成，并将优化人IPS衍生的棕色的热能力 通过修改BMP信号传导来脂肪细胞。该项目与肥胖有关 及其相关的合并症。项目2（M. Reagan）解决了骨髓的起源和功能 脂肪组织，一个独特的仓库，在骨质疏松和肥胖症中得到增强，可能有助于骨骼 脆弱性。该项目将检验骨细胞衍生的硬化素促进骨髓的新假设 通过抑制Wnt信号传导的脂肪形成，并将利用生物工程方法和小鼠模型 骨生理的改变。项目3（C. Duarte）是一个翻译项目，解决了问题的后果 骨折风险的非典型抗精神病药。非典型抗精神病药，例如利培酮（RIS）高度 针对精神病和行为症状的规定，具有副作用，包括骨质流失，增加 断裂风险和体重增加。该项目将研究护士家庭居民，包括RIS的普遍用户 和β受体阻滞剂，仅在动物研究中就显示出对骨质流失的受保护作用。这个项目将确定 如果与仅RIS相比，RIS和β受体阻滞剂的组合减少了断裂的风险。项目4（K. Motyl）已完成项目3，并使用鼠标模型测试了RIS作用于 中枢神经系统直接靶向骨质流失或通过激活棕色脂肪组织。这个项目 提议对骨骼的大脑区域中RIS进行了新的分析，还检验了以下假设。 诱导的棕色脂肪组织的激活反过来可以介导骨质流失。这些项目将得到 强调科学合作并继续的行政和专业发展核心 专业发展和三个科学核心：（i）蛋白质组学和脂质核心（C. vary），（ii） 组织病理学和组织形态计量学核心（V. Lindner）和（iii）生理学核心 代谢网络的间充质和神经调节（C. Rosen）。