Il-6 and metabolic crosstalk between tissues

Il-6 和组织之间的代谢串扰

• 批准号: 9032178
• 负责人: Shannon Marie Reilly
• 金额: $ 16.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-16 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032178
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Advisory Committees; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Attention; Basic Science; Biological Sciences; Breeding; Cells; ChIP-seq; Chronic; Clinical; Collaborations; Data; Dependence; Development; Diet; Disease; Educational workshop; Environment; Equilibrium; Exhibits; Faculty; Fatty acid glycerol esters; Gluconeogenesis; Glucose; Goals; Health Sciences; Hepatic; Homeostasis; Immune; Inflammation; Inflammation Mediators; Inflammatory; Institutes; Institution; Insulin; Insulin Resistance; Intestines; K-Series Research Career Programs; Knockout Mice; Laboratories; Lead; Link; Lipids; Liver; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Michigan; Molecular; Muramidase; Mus; Muscle; Obese Mice; Obesity; Pancreas; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Physicians; Play; Population; Positioning Attribute; Process; Public Health; Regulation; Research; Research Personnel; Resolution; Resources; Risk Factors; Role; Sequence Analysis; Serum; Signal Transduction; Skeletal Muscle; Source; System; TBK1 gene; Tissues; Translations; Universities; Visceral; adrenergic; amlexanox; blood glucose regulation; career; career development; chromatin immunoprecipitation; collaborative environment; cytokine; deep sequencing; feeding; glucose metabolism; glucose production; glucose uptake; hepatic gluconeogenesis; improved; in vivo; novel therapeutic intervention; prevent; public health relevance; response; skills; subcutaneous; transcriptome sequencing

 DESCRIPTION (provided by applicant): There is accumulating evidence that the chronic-low grade inflammation associated with obesity plays an important role in the development of metabolic disease. Although a number of molecular pathways connecting inflammation and metabolism have been discovered, numerous gaps remain in our understanding of how inflammatory signals disrupt normal glucose and lipid homeostasis, particularly concerning the role of different cytokines. This is especially true of the classic inflammatory cytokine, Il-6. Although elevated Il-6 levels are a risk factor for the development of metabolic disease, numerous beneficial effects of the cytokine on glucose metabolism have been observed. Il-6 appears to be is a key player in a subcutaneous adipose tissue:hepatic axis, whereby Il-6 secreted from subcutaneous adipose tissue suppresses hepatic gluconeogenesis via the phosphorylation and activation of Stat3. The noncanonical IκB kinases Ikk-ε and Tbk1, which are induced downstream of the inflammatory mediator NF-κB, suppress this axis in the obese state. Inhibition of Ikk-ε/Tbk1 by the drug amlexanox restores the balance of this axis, providing an ideal system for investigating the in vivo effects of Il-6 signaling in the context of obesity. Using this established system, Il-6 signaling and its effects on metabolic disease will be examined. The first aim will focus on the hepatic effects of Il-6 and their dependence on hepatic Stat3 activation. The second aim will investigate the extra hepatic effects of Il-6 signaling on glucose metabolism, looking into the regulation of glucose handling in peripheral tissues and the specific role of Glp-1 in the pancreas. The third aim will focus on Il-6 signaling within the adipoe tissue, from adipocytes to immune cells. The applicant's long-term career goal is to make a significant contribution to the understanding of the pathology of obesity and the development of metabolic disease. This career development award will enable the applicant to develop the skills required to become an independent investigator, leading a basic research laboratory at an academic institution in a tenure track faculty position, where the applicant will have the best chance of achieving her long-term goal. These skills will be developed at the University of Michigan, an excellent environment in which to perform health sciences related research, with many available resources including career development workshops. The Life Sciences Institute provides a fantastic collaborative environment in which to perform basic research with translational potential. Collaborations between faculty and physicians provide opportunities for the translation of basic research into the clinical setting. The applicant will utilize the resourcs available at the University of Michigan, as well as guidance and support of the Mentoring and Advisory Committees, to complete the proposed research, and develop as an independent investigator.

 描述（由申请人提供）：越来越多的证据表明，与肥胖相关的慢性低度炎症在代谢疾病的发展中起着重要作用，尽管已经发现了许多连接炎症和代谢的分子途径，但仍存在许多空白。我们了解炎症信号如何破坏正常的葡萄糖和脂质稳态，特别是对于经典炎症细胞因子 IL-6 的作用尤其如此，尽管 IL-6 水平升高是代谢性疾病发生的危险因素。疾病，已观察到细胞因子对葡萄糖代谢的许多有益作用，IL-6 似乎是皮下脂肪组织：肝轴的关键参与者，因此皮下脂肪组织分泌的 Il-6 通过磷酸化和活化抑制肝糖异生。 Stat3。在炎症介质 NF-κB 下游诱导的非经典 IκB 激酶 Ikk-ε 和 Tbk1 在肥胖者中抑制该轴。药物 amlexanox 对 Ikk-ε/Tbk1 的抑制可恢复该轴的平衡，从而提供。 一个研究肥胖背景下 Il-6 信号传导体内影响的理想系统 使用这个已建立的系统，将检查 Il-6 信号传导及其对代谢疾病的影响。 -6 及其对肝脏 Stat3 激活的依赖性。第二个目标是研究 Il-6 信号对葡萄糖代谢的额外肝脏影响，研究外周组织中葡萄糖处理的调节以及 Glp-1 在胰腺中的具体作用。这第三个目标将重点关注从脂肪细胞到免疫细胞的脂肪组织内的 IL-6 信号传导。申请人的长期职业目标是为了解肥胖的病理学和代谢疾病的发展做出重大贡献。发展奖将使申请人能够培养成为独立研究员所需的技能，在学术机构担任终身教职，领导基础研究实验室，申请人将有最好的机会实现其长期目标。将在密歇根大学开发，生命科学研究所提供了进行健康科学相关研究的绝佳环境，拥有许多可用资源，包括职业发展研讨会，为开展具有转化潜力的基础研究提供了绝佳的合作环境。教师和医生之间的合作为转化提供了机会。申请人将利用密歇根大学的可用资源以及指导和咨询委员会的指导和支持来完成拟议的研究，并发展成为一名独立研究者。