Peripheral and Central Inflammatory Signals in the Sickness Response

描述(申请人提供)：疾病反应中的外周和中枢炎症信号这项申请调查了炎症诱导的负能量平衡是由依赖于脑组织内的细胞因子信号通路的机制调节的假说。全身性炎症可以显著减轻体重，但在疾病中是否需要细胞因子仍不清楚，炎症和神经元能量平衡调节器之间的相互作用也尚不清楚。具体目的是通过确定1)脑组织中的炎症信号是否是调节疾病反应所必需的和充分的，以及神经元和内皮细胞中的炎症信号是否是导致疾病发生所必需的，以及2)下丘脑黑素皮质素信号是否是疾病发生所必需的，从而确定关键的炎症途径在介导疾病反应中的作用。为了实现这些目标，建议使用各种突变小鼠模型进行研究，使用申请者和参与该建议的咨询公司的实验室建立的方法来评估疾病，包括确定能量摄入和消耗，量化下丘脑和循环中的细胞因子，以及骨髓移植以改变循环免疫细胞的基因。这些目标对理解炎症影响能量平衡的机制做出了重要贡献，并可能确定从肥胖到慢性消耗性疾病等各种疾病的潜在治疗方法。

DESCRIPTION (provided by applicant): Peripheral and Central Inflammatory Signals in the sickness Response This application investigates the hypothesis that inflammation-induced negative energy balance is mediated by mechanisms dependent on cytokine signaling pathways within brain tissue. Systemic inflammatory conditions cause marked weight loss yet the necessity of cytokines in 'sickness' remains unclear and the interaction between inflammation and neuronal regulators of energy balance remains unknown. The Specific Aims seek to determine the role of key inflammatory pathways in mediating the 'sickness response' by determining 1) whether inflammatory signals in brain tissue are necessary and sufficient to mediate the sickness response', and whether inflammatory signaling in neurons and endothelial cells is necessary to cause 'sickness', and 2) whether hypothalamic melanocortin signaling is necessary for 'sickness' to occur. To accomplish these objectives, studies are proposed using a variety of mutant mouse models to evaluate 'sickness' using methods established in the laboratories of the applicant and the Consultants participating in this proposal, including determining energy intake and expenditure, quantifying hypothalamic and circulating cytokines and bone marrow transplantation to alter the genotype of circulating immune cells. These aims make an important contribution to understanding the mechanism whereby inflammation affects energy balance and may identify potential therapies for disorders ranging from obesity to chronic wasting illnesses.