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性细胞因子引起厌食，体重减轻和嗜睡的神经机制。这一发现的星座与许多慢性疾病相关的浪费状态非常相似。恶病质大幅度降低了生活质量，并增加了死亡率和发病率。此外，目前尚无有效的治疗方法。先前的工作已经确定，炎症细胞因子的中央给药可以重新创建卡希克西亚的所有基本特征。尽管已经描述了一种炎性细胞因子IL-1B引起代谢变化的机制，但目前尚不清楚其他厌食症细胞因子是否以相同的方式起作用。拟议研究的具体目的I将评估白血病抑制因子（LIF），慢性疾病中炎症性细胞因子是否通过直接激活下刺刺激核中核核元中的促蛋白酶素（POMC）神经元来降低食物摄入量并降低食物摄入量并提高代谢率。这将通过使用组织化学方法验证POMC神经元上的LIF激活的解剖基础来测试这一点。这些神经元在LIF存在下的反应将在体内和Ex Vivo中受到监测，并将与野生型和转基因小鼠的整个动物生理学相关，这些小鼠在ARCUTUATE POMC神经元中缺乏LIF信号传导。还没有描述炎症引起嗜睡的手段。最近的研究暗示了Orexin神经元在唤醒和嗜睡的维持中的作用。特定的目标II将检验以下假设：降低Orexin神经元活性会介导炎症引起的嗜睡。使用慢性炎症的肿瘤轴承模型，在组织化学上，Orexin神经元的活性将与运动活性，食物摄入和身体组成的测量相关。还将使用中央细胞因子给药模型，并将评估Orexin替代恢复活性和喂养行为的有效性。 病虫气是许多慢性疾病晚期常见的浪费综合征，严重限制了 患者能够抗衡病情或接受治疗的能力。尽管据估计卡氏症会影响多达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降低，以此作为开发新疗法的一种手段。