The Effects of Oncostatin M on the Adipose Tissue Extracellular Matrix

 描述(申请人提供)：正常的AT重塑需要细胞外基质(ECM)蛋白复杂网络的合成和降解之间的平衡。在肥胖症中观察到的这种平衡的破坏会导致AT纤维化和炎症。我们已经报道，OSM是一种gp130细胞因子，由AT巨噬细胞产生，在小鼠和人类肥胖中表达上调。我们的数据表明，在小鼠中，脂肪细胞特异性的OSM特异性受体(OSMR)敲除会导致胰岛素抵抗、糖耐量异常，并增加内脏AT中促纤维化和促炎基因的表达。拟议的AIMS将检验脂肪细胞OSMR信号丢失扰乱正常脂肪组织动态平衡并促进AT纤维化和胰岛素抵抗的总体假设。重要的是，Elks博士将在转基因小鼠的产生和表型、分子生物学以及AT-ECM的生化评估和成像方面学习和实施新的方法，这些都是她作为研究人员独立所必需的。彭宁顿生物医学研究中心将为Elks博士提供一个理想的学习环境，以成功完成拟议的目标和目标。该研究项目的培训还将为未来的项目提供基础，以评估代谢性疾病中AT-ECM生物学和脂肪细胞代谢的变化，并将研究结果应用于胰岛素抵抗和肥胖的新疗法的开发，这是Elks博士的长期研究目标。PI组建了一支由经验丰富的调查人员和合作者组成的优秀指导团队，他们都将提供指导和专业知识，帮助她实现独立。

 DESCRIPTION (provided by applicant): Normal AT remodeling requires a balance between the synthesis and degradation of a complex network of extracellular matrix (ECM) proteins. Disruption of this balance, as observed in obesity, can lead to AT fibrosis and inflammation. We have reported that oncostatin M (OSM), a gp130 cytokine, is produced by AT macrophages and up-regulated in mouse and human obesity. Our data demonstrate that adipocyte-specific knockout of the OSM-specific receptor (OSMR) in mice leads to insulin resistance, glucose intolerance, and increased pro-fibrotic and pro-inflammatory gene expression in visceral AT. The proposed aims will test the overall hypothesis that that loss of adipocyte OSMR signaling disrupts normal adipose tissue homeostasis and promotes AT fibrosis and insulin resistance. Importantly, Dr. Elks will learn and implement new methods in transgenic mouse generation and phenotyping, molecular biology, and the biochemical assessment and imaging of the AT-ECM that are necessary for her independence as an investigator. Pennington Biomedical Research Center will provide an ideal learning environment for Dr. Elks to successfully complete the proposed aims and objectives. The training in this research project will also provide a basis for future projects to assess alterations in AT-ECM biology and adipocyte metabolism in metabolic diseases, and to apply findings to the development of novel therapies for insulin resistance and obesity, which is Dr. Elks' long-term research goal. The PI has assembled an outstanding mentoring team of experienced investigators and collaborators who will all provide their guidance and expertise to help her achieve independence.