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).

全身代谢受多个器官系统的整合调节，包括脂肪组织， 骨骼和骨髓这些组织调节的不平衡导致慢性疾病， 肥胖症和骨质疏松症。脂肪细胞和骨祖细胞共享共同的间充质前体， 将这两种流行病联系起来间充质祖细胞在衰老过程中也受到严格调控， 营养压力和快速的温度变化。越来越多的人认识到， 系统在这种代谢调节中发挥着独特的作用，无论是在健康还是在疾病状态下。我们的整体 该项目的目标是确定整合大脑、骨骼和脂肪的特定分子和信号通路 组织在调节代谢网络中的作用。这个由露西·廖博士和克利福德·罗森博士领导的COBRE项目， 汇集了四个项目，测试脂肪细胞和骨骼代谢功能的互补方面， 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 棕色脂肪生成和产热，并将优化人类iPS衍生棕色脂肪的产热能力。 通过改变BMP信号传导。这个项目在肥胖症方面具有很高的转化意义 及其相关的并发症。项目2（M.里根）地址的起源和功能的骨髓 脂肪组织是一种独特的储存库，在骨质疏松症和肥胖症中得到增强， 脆弱该项目将测试新的假设，即骨细胞衍生的硬化素促进骨髓 脂肪形成通过抑制Wnt信号传导，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， 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，如利培酮（RIS）， 处方精神和行为症状，并有副作用，包括骨质流失，增加 骨折风险和体重增加。这个项目将研究疗养院的居民，包括RIS的普遍用户 和β-受体阻滞剂，在动物研究中单独使用它们对骨丢失有保护作用。该项目将决定 如果与单独使用RIS相比，RIS和β受体阻滞剂联合使用可降低骨折风险。项目4（K. Motyl）是项目3的补充，并使用小鼠模型来测试RIS作用于 中枢神经系统直接或通过激活棕色脂肪组织来靶向骨丢失。这个项目 提出了新的分析RIS的大脑区域，支配骨骼，也测试假设，RIS- 棕色脂肪组织的诱导活化又可介导骨损失。这些项目将得到以下方面的支持： 一个行政和专业发展核心，强调科学合作，并继续 专业发展和三个科学核心：（i）蛋白质组学和脂质组学核心（C。（ii） 组织学和组织形态学核心（V. Lindner），以及（iii） 代谢网络的间充质和神经调节COBRE（C。罗森）。