Il-6 and metabolic crosstalk between tissues

 描述(申请人提供)：有越来越多的证据表明，与肥胖相关的慢性-低度炎症在代谢性疾病的发展中起着重要作用。虽然已经发现了许多连接炎症和新陈代谢的分子途径，但对于炎症信号如何破坏正常的糖脂平衡，特别是不同细胞因子的作用，我们的理解仍然存在许多空白。经典的炎性细胞因子IL-6尤其如此。虽然IL-6水平升高是代谢性疾病发展的危险因素，但已观察到该细胞因子对葡萄糖代谢的许多有益影响。IL-6似乎是皮下脂肪组织-肝轴的关键角色，皮下脂肪组织分泌的IL-6通过STAT3的磷酸化和激活抑制肝脏的糖异生。非规范的I-κB激酶IKK-ε和Tbk1是在炎症介质NF-κB下游诱导的，在肥胖状态下抑制这一轴。药物氨来昔诺对IKK-ε/Tbk1的抑制可恢复这一轴的平衡，提供 这是研究IL-6信号在肥胖背景下的体内效应的理想系统。利用这个已建立的系统，将研究IL-6信号及其在代谢性疾病中的作用。第一个目标将集中在IL-6对肝脏的影响及其对肝脏STAT3激活的依赖。第二个目标是研究IL-6信号在肝外对葡萄糖代谢的影响，探讨外周组织中葡萄糖的调节以及GLP-1在胰腺中的具体作用。第三个目标将集中在脂肪组织内的IL-6信号，从脂肪细胞到免疫细胞。申请者的长期职业目标是为了解肥胖的病理和代谢性疾病的发展做出重大贡献。这一职业发展奖将使申请者能够发展成为一名独立调查员所需的技能，领导学术机构的基础研究实验室担任终身教职，在那里申请者将有最大机会实现她的长期目标。这些技能将在密歇根大学培养，这是一个进行健康科学相关研究的良好环境，拥有包括职业发展研讨会在内的许多可用资源。生命科学研究所提供了一个极好的协作环境，可以在其中进行具有翻译潜力的基础研究。教师和医生之间的合作为将基础研究转化为临床环境提供了机会。申请者将利用密歇根大学现有的资源，以及指导和咨询委员会的指导和支持，完成拟议的研究，并发展成为一名独立的调查人员。

 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.