Inflammatory Cytokine regulation of POMC and Orexin neurons in cachexia.

描述（由申请人提供）： 本研究的目的是了解炎症细胞因子引起厌食、体重减轻和嗜睡的神经机制。这一系列发现与恶病质非常相似，恶病质是许多慢性疾病常见的疾病相关性消耗状态。恶病质显著降低生活质量并增加死亡率和发病率。此外，目前还没有有效的治疗方法。先前的工作已经确定，炎性细胞因子的中枢给药可以重现恶病质的所有主要特征。虽然一种炎症细胞因子IL-1b引起代谢变化的机制已被描述，但目前尚不清楚其他厌食细胞因子是否以同样的方式起作用。本研究的具体目标I将评估白血病抑制因子（LIF），一种在慢性疾病中升高的炎性细胞因子，是否通过直接激活下丘脑弓状核中的阿黑皮素原（POMC）神经元来减少食物摄入和增加代谢率。这将通过使用组织化学方法验证POMC神经元上存在LIF激活的解剖学基础来进行测试。将在体内和离体监测这些神经元在LIF存在下的反应，并将其与弓形POMC神经元中LIF信号传导缺陷的野生型和转基因小鼠中的整个动物生理学相关。炎症引起嗜睡的方式也没有被描述。最近的研究表明食欲素神经元在维持觉醒和嗜睡中的作用。具体目标II将测试食欲素神经元活性降低介导炎症诱导的嗜睡的假设。使用慢性炎症的荷瘤模型，将组织化学地评估食欲素神经元的活性，并将其与运动活动、食物摄入和身体组成的测量相关联。还将利用恶病质的中枢细胞因子施用模型，并将评价食欲素替代在恢复活动和进食行为中的有效性。 恶病质是一种常见于许多慢性疾病晚期的消耗性综合征，严重限制了患者的健康。 患者对抗疾病或接受治疗的能力。虽然恶病质估计影响多达2%的人口，但目前没有有效的治疗方法。这项研究旨在了解疾病如何导致饮食和活动水平的破坏性减少，以此作为开发新疗法的手段。

DESCRIPTION (provided by applicant): The goal of this research is to understand the neural mechanisms by which inflammatory cytokines cause anorexia, weight loss, and lethargy. This constellation of findings closely resembles cachexia, a state of disease-associated wasting common to many chronic diseases. Cachexia dramatically reduces quality of life and increases mortality and morbidity. Further, there are currently no effective treatments available. Previous work has established that central administration of inflammatory cytokines can recreate all of the cardinal features of cachexia. Though the mechanism by which one inflammatory cytokine, IL-1b, causes the metabolic changes has been described, it is currently unknown whether other anorectic cytokines work in the same way. Specific aim I of the proposed research will evaluate whether leukemia inhibitory factor (LIF), an inflammatory cytokine elevated in chronic disease, reduces food intake and increases metabolic rate by directly activating proopiomelanocortin (POMC) neurons in the arcuate nucleus ofthe hypothalamus. This will be tested by verifying an anatomic basis for LIF activation exists on POMC neurons using histochemical approaches. The response of these neurons in the presence of LIF will be monitored in vivo and ex vivo and will be correlated to whole animal physiology in wild-type and transgenic mice which are deficient in LIF signaling in arcuate POMC neurons. The means by which inflammation causes lethargy also have not been described. Recent research has implicated the role of orexin neurons in the maintenance of arousal and somnolence. Specific aim II will test the hypothesis that a decrease in orexin neuron activity mediates inflammation-induced lethargy. Using a tumor bearing model of chronic inflammation, activity of orexin neurons will be evauated histochemically and correlated to measurements of motor activity, food intake, and body composition. A central cytokine administration model of cachexia will also be utilized, and the effectiveness of orexin replacement in restoring activity and feeding behavior will be evaluated. Cachexia, a wasting syndrome common to the late stages of many chronic diseases, severely limits a patient's ability to fight their condition or receive treatment. Though cachexia is estimated to affect as much as 2% of the population, there is currently no effective treatment. This research is designed to understand how disease causes these devastating reductions in eating and activity level as a means to develop new therapies.