Inflammatory Cytokine regulation of POMC and Orexin neurons in cachexia.

描述(由申请人提供)： 这项研究的目的是了解炎性细胞因子引起厌食、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，恶病质是一种与疾病相关的消瘦状态，在许多慢性病中很常见。恶病质极大地降低了生活质量，增加了死亡率和发病率。此外，目前还没有有效的治疗方法。先前的研究已经证实，中央注射炎性细胞因子可以重现恶病质的所有基本特征。虽然一种炎性细胞因子IL-1b引起代谢变化的机制已经被描述，但目前还不清楚其他厌食性细胞因子是否以同样的方式发挥作用。这项拟议研究的具体目标I将评估白血病抑制因子(LIF)是否通过直接激活下丘脑弓状核中的前阿片黑素皮质素(POMC)神经元来减少食物摄入量和提高代谢率。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检验。这些神经元在LIF存在下的反应将在体内和体外进行监测，并将与野生型和转基因小鼠的整体动物生理相关，这些小鼠的弓状POMC神经元中缺乏LIF信号。炎症导致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起着重要作用。《特殊目的II》将检验食欲素神经元活性降低会导致炎症导致嗜睡的假设。利用慢性炎症的肿瘤模型，组织化学将评估增食欲素神经元的活性，并将其与运动活动、食物摄入量和身体成分的测量相关联。还将利用恶病质的中枢细胞因子给药模型，并将评估食欲素替代在恢复活动和摄食行为方面的有效性。 恶病质是许多慢性病晚期常见的一种消瘦综合征，严重限制了 患者对抗病情或接受治疗的能力。尽管恶病质估计影响多达2%的人口，但目前还没有有效的治疗方法。这项研究旨在了解疾病如何导致进食和活动水平的破坏性下降，以此作为开发新疗法的一种手段。

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.