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的调节失衡会导致慢性疾病，例如 肥胖和骨质疏松症。脂肪细胞和骨祖细胞具有共同的间充质前体细胞，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调控， 人们越来越认识到交感神经会受到营养压力和温度快速变化的影响。 无论是在健康还是在疾病状态下，系统在这种代谢调节中都发挥着独特的作用。 项目目标是定义整合大脑、骨骼和脂肪的特定分子和信号通路 该 COBRE 项目由 Lucy Liaw 和 Clifford Rosen 博士领导， 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，以及 项目 1（A. Brown）将研究 BMP 信号传导在中枢神经系统输入中的作用。 棕色脂肪生成和产热作用，并将优化人类 iPS 衍生棕色的产热能力 通过修改 BMP 信号传导来调节脂肪细胞 该项目对于肥胖具有重要的转化意义。 及其相关的合并症项目 2（M. Reagan）探讨了骨髓的起源和功能。 脂肪组织是一种独特的储存库，在骨质疏松症和肥胖症中会增强，并可能有助于骨骼健康 该项目将测试骨细胞衍生的硬化素促进骨髓的新假设。 通过抑制 Wnt 信号传导来促进脂肪生成，并将利用生物工程方法和小鼠模型 改变骨骼生理学的项目 3（C. Duarte）是一个解决以下问题的转化项目。 非典型抗精神病药物如利培酮 (RIS) 的骨折风险很高。 用于治疗精神和行为症状，并具有副作用，包括骨质流失、增加 该项目将研究疗养院居民，包括 RIS 的普遍使用者。 和β-受体阻滞剂，该项目将在动物研究中确定它们对骨质流失的保护作用。 与单独使用 RIS 相比，RIS 和 β 受体阻滞剂的组合是否可以降低骨折风险（K. Motyl）是项目3的补充，并使用小鼠模型来测试RIS作用的新假设 该项目通过中枢神经系统直接或通过激活棕色脂肪组织来针对骨质流失。 对大脑中 RIS 区域的新颖分析表明，RIS 神经支配骨骼，并且还检验了 RIS- 的假设 棕色脂肪组织的诱导激活反过来可以介导骨质流失，这些项目将得到支持。 强调科学合作和持续的行政和专业发展核心 专业发展和三个科学核心：(i) 蛋白质组学和脂质组学核心 (C. Vary)，(ii) 组织病理学和组织形态计量学核心 (V. Lindner)，以及 (iii) 生理学核心 代谢网络的间充质和神经调节 COBRE（C. Rosen）。