Characterization of a receptor mediating adiponectin functions on bone

介导骨脂联素功能的受体的表征

基本信息

批准号：
9118629
负责人：
Gerard Karsenty
金额：
$ 44.01万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118629
关键词：
Address Adipocytes Affect Age-Related Bone Loss Animal Feed Animals Antibodies Apoptosis Biochemical Biological Biological Assay Biology Blood - brain barrier anatomy Bone Diseases Bone Formation Inhibition Bone remodeling Brain Cells Ceramides Collagen Collagen Receptors Communication DDR1 gene Data Diet Disease Energy Metabolism Evolution Fatty acid glycerol esters Gene Deletion Generations Genes Goals H-Cadherin Health Hepatocyte Hormone Receptor Hormone use Hormones Human Human Genetics Insulin Receptor Kinetics Lead Leptin Mediating Molecular Mus Myoblasts Nerve Neurons Organ Osteoblasts Osteocalcin Osteogenesis Osteoporosis Phenotype Phosphorylation Physiological Processes Physiology Protein Tyrosine Phosphatase Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Receptor Signaling Recruitment Activity Regulation Relative (related person)Signal Pathway Signal Transduction Sympathetic Nervous System Testing Therapeutic Time Translating Ursidae Family Vision Whole Organism adiponectin age related base bone bone mass design discoidin domain receptor 2 discoidin receptor feeding in vivo inhibiting antibody interest knock-down locus ceruleus structure mouse genome mouse model novel prevent receptor skeletal transcription factor

项目摘要

DESCRIPTION (provided by applicant): We have been interested in recent years in the biology of the most abundant adipokine, adiponectin. In addressing what could be the functions(s) of adiponectin in animals fed a normal diet we considered the fact that adiponectin appears during evolution with bone and is regulated by the bone-derived hormone osteocalcin. We then asked whether adiponectin was regulating bone mass. Our results obtained in vivo showed that 1) adiponectin inhibits bone formation by acting directly on osteoblasts while it favors bone formation by inhibiting the sympathetic nerves through its signaling in the brain; 2) none of the known receptors for adiponectin seem to mediate any of these two functions and adiponectin does not recruit AMPK and does not regulate ceramide activity in osteoblasts; 3) the signaling pathway triggered by adiponectin in osteoblasts suggested that the receptor for this hormone in osteoblasts is a receptor tyrosine kinase. Further analysis presented in this application strongly suggest, based on molecular and biochemical grounds, that the receptor for adiponectin in osteoblasts and possibly in neurons of the locus coeruleus may be the discoidin receptor 2 (DDR2), a RTK with a slow kinetic of phosphorylation. Based on preliminary findings presented in this application we now propose to test this hypothesis in vivo. The specific aims of this application are: To demonstrate that DDR2 mediates adiponectin signaling in osteoblasts. To demonstrate that in vivo FoxO1 lies downstream of DDR2-dependent signaling in osteoblasts. To determine in vivo the biological significance of the interactions occurring between DDR2, AdipoR1 and T-cadherin. To demonstrate in vivo that DDR2 and/or DDR1 mediates adiponectin signaling in neurons of the locus coeruleus.

描述（由适用提供）：近年来，我们对最丰富的脂肪因子脂联素的生物学感兴趣。在解决喂养正常饮食的动物中脂联素的功能时，我们认为脂联素在骨骼进化过程中出现在骨骼进化过程中，并且受骨衍生的霍斯烯骨钙钙蛋白的调节。然后，我们询问脂联素是否控制骨骼质量。我们在体内获得的结果表明，1）脂联素通过直接作用于成骨细胞来抑制骨形成，同时通过通过大脑中的信号抑制交感神经系统来促进骨形成； 2）脂联素的已知受体似乎都没有介导这两个功能中的任何一种，脂联素不募集AMPK，也不调节成骨细胞中的神经酰胺活性。 3）脂联素在成骨细胞中触发的信号传导途径表明，在成骨细胞中该赛马的受体是一种受体酪氨酸激酶。在该应用中提出的进一步分析强烈地表明，基于分子和生化基础，成骨细胞中脂联素的受体以及在层层基因座的神经元中可能的受体可能是盘状受体2（ddr2），一种rtk，rtk的磷酸化速度缓慢。基于本应用程序中提出的初步发现，我们现在建议在体内检验该假设。该应用的具体目的是：证明DDR2介导成骨细胞中的脂联素信号传导。为了证明体内FOXO1位于成骨细胞中DDR2依赖性信号的下游。为了确定体内DDR2，adipor1和t-钙粘着蛋白之间发生相互作用的生物学意义。在体内证明DDR2和/或DDR1介导位点神经元中的脂联素信号传导。