Peripheral and Central Inflammatory Signals in the Sickness Response

描述（由申请人提供）：疾病反应中的外周和中枢炎症信号该应用研究了炎症诱导的负能量平衡是由依赖于脑组织内细胞因子信号传导途径的机制介导的假设。全身性炎症条件导致显着的体重减轻，但在“疾病”的细胞因子的必要性仍然不清楚，炎症和能量平衡的神经元调节器之间的相互作用仍然未知。具体目的旨在通过确定1）脑组织中的炎症信号是否是介导“疾病反应”所必需和充分的，以及神经元和内皮细胞中的炎症信号是否是引起“疾病”所必需的，以及2）下丘脑黑皮质素信号是否是发生“疾病”所必需的，来确定关键炎症通路在介导“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，以使用申请人和参与本提案的顾问的实验室中建立的方法评估“疾病”，包括确定能量摄入和消耗，定量下丘脑和循环细胞因子以及骨髓移植以改变循环免疫细胞的基因型。这些目标为理解炎症影响能量平衡的机制做出了重要贡献，并可能为从肥胖到慢性消耗性疾病的疾病确定潜在的治疗方法。

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.