Melanocortins, Energy Balance and Cancer Anorexia

黑皮质素、能量平衡和癌症厌食症

• 批准号: 7017716
• 负责人: BRENT E WISSE
• 金额: $ 12.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017716
• 关键词: Adenoviridae; anorexia; bioenergetics; cancer complication; disease /disorder model; genetically modified animals; hormone inhibitor; hormone regulation /control mechanism; hypothalamus; in situ hybridization; laboratory mouse; laboratory rat; lipopolysaccharides; melanocyte stimulating hormone; pituitary hormones; proopiomelanocortin; transfection

DESCRIPTION (provided by applicant) The purpose of this application is to define the central mechanisms that lead to decreased appetite and weight loss in conditions of pathologic anorexia. Our previous work supports the hypothesis that tumors and other inflammatory stimuli cause anorexia via a mechanism dependent on signaling by melanocortins, brain peptides that regulate food intake under physiologic conditions. Signals elaborated by the tumor cells are proposed to increase melanocortin receptor signaling, an inappropriate 'satiety' signal which causing negative energy balance, and leading to inexorable weight loss. The potency of the effect of cancer on energy homeostasis through the melanocortin system is highlighted by the fact that compensatory changes engendered by weight loss, such as decreases in serum leptin, are unable to effect the normal hypothalamic responses that stimulate a return to the baseline body weight. The first major objective of this application is to identify the components of the melanocortin system that are up-regulated in rodent models of cancer anorexia. This will be accomplished by 1) testing if pro-opiomelanocortin (POMC) in the arcuate nucleus (ARC) is both necessary and sufficient for cancer anorexia to occur, using both gene knock-out model and adenoviral gene therapy models, respectively; 2) determining if signaling by agouti-related peptide (Agrp), the endogenous melanocortin antagonist, is reduced, through in situ hybridization studies; and 3) determining if down-regulation of melanin concentrating hormone (MCH) is a consequence of melanocortin signaling and mediates anorexia, using in situ hybridization as well as adenoviral gene therapy studies. The second major objective is to investigate whether anorexia induced by an inflammatory stimulus, lipopolysaccharide (LPS) injection, involves the same melanocortin-dependent mechanism involved in cancer anorexia by using experimental strategies similar to the ones outlined above. By improving our understanding of the mechanism of cancer anorexia, these studies will help to identify potential central targets for the treatment of obesity as well as characterizing strategies for the treatment of anorexia in chronic disease states. This research will prepare the applicant for an academic career as an independent investigator in the field of energy homeostasis. The transition to independence will be facilitated by the rich training environment afforded by Dr. Schwartz and the Harborview Medical Center Energy Metabolism Laboratory, and by joining a large community of productive researchers in the field of energy homeostasis across the University of Washington campus.

描述(由申请人提供) 本应用程序的目的是定义导致 在病理性厌食症的情况下，食欲下降和体重减轻。我们的 以前的工作支持肿瘤和其他炎症性疾病 刺激通过一种依赖于黑素皮质素信号的机制导致厌食症， 在生理条件下调节食物摄入量的脑多肽。信号 所阐述的肿瘤细胞均建议增加黑素皮质素受体 信号，一种不适当的“饱腹感”信号，会导致负能量 平衡，并导致势不可挡的减肥。其效果的效力 通过黑素皮质素系统实现能量动态平衡的癌症突出表现为 体重减轻引起的补偿性变化的事实，如减少 在血清瘦素中，不能影响正常的下丘脑反应 刺激恢复到基线体重。 这个应用程序的第一个主要目标是识别 在啮齿动物癌症模型中上调的黑素皮质素系统 厌食症。这将通过1)测试促阿片黑素皮质醇 弓状核(ARC)中的POMC对于癌症来说既是必要的也是充分的 同时使用基因敲除模型和腺病毒基因治疗将发生厌食症 模型；2)确定是否通过刺鼠相关肽传递信号 内源性黑素皮质素拮抗剂(AgRP)通过原位减少 杂交研究；以及3)确定黑色素是否下调 浓缩激素(MCH)是黑素皮质素信号转导和 利用原位杂交和腺病毒基因介导厌食症 治疗研究。第二个主要目标是调查厌食症 由炎性刺激，脂多糖(LPS)注射诱导， 涉及与癌症厌食症有关的相同的黑素皮质素依赖机制 通过使用与上面概述的类似的实验策略。 通过提高我们对癌症厌食症机制的理解，这些 研究将有助于确定潜在的治疗中心靶点 肥胖症及其治疗厌食症的特征策略 慢性疾病状态。这项研究将为申请者准备参加 作为能源领域的独立研究员的学术生涯 动态平衡。向独立的过渡将由富人推动 由Schwartz博士和Harborview医疗中心提供的培训环境 能量代谢实验室，并通过加入一个大型生产力社区 芝加哥大学能量动态平衡领域的研究人员 华盛顿校区。