Inflammatory Cytokine regulation of POMC and Orexin neurons in cachexia.

恶病质中 POMC 和食欲素神经元的炎症细胞因子调节。

• 批准号: 7750905
• 负责人: Aaron Grossberg
• 金额: $ 4.3万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750905
• 关键词: Acute; Affect; Anatomy; Animals; Anorexia; Anus; Appetite Depressants; Arousal; Basal metabolic rate; Behavior; Body Composition; Body Weight decreased; Brain; Cachexia; Canis familiaris; Characteristics; Chronic; Chronic Disease; Chronically Ill; Cystic Fibrosis; Cytokine Receptors; Cytotoxic Chemotherapy; Data; Disease; Drowsiness; Eating; Effectiveness; Event; Exhibits; Feeding behaviors; Goals; HIV; Heart failure; Hypothalamic structure; In Situ Hybridization; Inflammation; Inflammatory; Infusion procedures; Interleukin-1 beta; Intervention; Lead; Life; Literature; Maintenance; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator of activation protein; Melanocortin 4 Receptor; Messenger RNA; Metabolic; Modeling; Monitor; Morbidity - disease rate; Motor Activity; Narcolepsy; Neural Pathways; Neurons; Neuropeptides; Operative Surgical Procedures; Patients; Peptides; Pharmacologic Substance; Physiology; Play; Population; Pro-Opiomelanocortin; Proteins; Quality of life; Regulation; Research; Role; Secondary to; Severities; Signal Transduction; Staging; Structure of nucleus infundibularis hypothalami; Synaptic Receptors; Testing; Transgenic Mice; Uremia; Wasting Syndrome; Work; base; chronic leukemia; cytokine; design; effective therapy; fighting; hypocretin; improved; in vivo; insight; leukemia inhibitory factor; leukemia inhibitory factor receptor; mortality; neuromechanism; receptor; response; therapeutic target; tumor; wasting

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.

描述（由申请人提供）： 这项研究的目的是了解炎症细胞因子导致厌食、体重减轻和嗜睡的神经机制。这一系列的发现与恶病质非常相似，恶病质是许多慢性疾病中常见的一种与疾病相关的消耗状态。恶病质显着降低生活质量并增加死亡率和发病率。此外，目前尚无有效的治疗方法。先前的研究已经证实，集中施用炎症细胞因子可以重现恶病质的所有主要特征。尽管一种炎性细胞因子 IL-1b 引起代谢变化的机制已经被描述，但目前尚不清楚其他厌食细胞因子是否也以同样的方式发挥作用。该研究的具体目标一是评估白血病抑制因子（LIF）（一种在慢性疾病中升高的炎症细胞因子）是否通过直接激活下丘脑弓状核中的阿片黑皮质素原（POMC）神经元来减少食物摄入并增加代谢率。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。这些神经元在 LIF 存在下的反应将在体内和离体进行监测，并将与弓形 POMC 神经元中缺乏 LIF 信号传导的野生型和转基因小鼠的整个动物生理学相关。炎症导致嗜睡的方式也尚未被描述。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 将检验食欲素神经元活动减少介导炎症引起的嗜睡的假设。使用慢性炎症的肿瘤荷瘤模型，可以对食欲素神经元的活性进行组织化学评估，并将其与运动活动、食物摄入和身体成分的测量结果相关联。还将利用恶病质的中枢细胞因子施用模型，并评估食欲素替代在恢复活动和进食行为方面的有效性。 恶病质是许多慢性疾病晚期常见的一种消耗综合征，严重限制了 患者抵抗病情或接受治疗的能力。尽管据估计恶病质影响多达 2% 的人口，但目前尚无有效的治疗方法。这项研究旨在了解疾病如何导致饮食和活动水平的毁灭性减少，以此作为开发新疗法的手段。