Melanocortins, Energy Balance and Cancer Anorexia

黑皮质素、能量平衡和癌症厌食症

• 批准号: 6853503
• 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/6853503
• 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） 该应用程序的目的是定义导致的中央机制 病理性厌食症中食欲下降和体重减轻。我们的 先前的工作支持肿瘤和其他炎症的假设 刺激通过依赖于黑皮质素信号传导的机制导致厌食症， 在生理条件下调节食物摄入的脑肽。信号 提出由肿瘤细胞精心制作以增加黑皮质素受体 信号传递，一种不适当的“饱腹感”信号，会导致负能量 平衡，并导致不可阻挡的减肥。效果的效力 癌症通过黑皮质素系统影响能量稳态 事实上，体重减轻引起的补偿性变化，例如体重减轻 血清瘦素中，无法影响正常的下丘脑反应 刺激体重回到基线。 该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皮质素系统 厌食症。这将通过以下方式完成：1) 测试阿片黑皮质素原是否 弓状核（ARC）中的（POMC）对于癌症来说既是必要的又是充分的 使用基因敲除模型和腺病毒基因治疗发生厌食症 型号分别； 2) 确定刺鼠相关肽是否信号传导 (Agrp)，内源性黑皮质素拮抗剂，通过原位减少 杂交研究； 3) 确定黑色素是否下调 浓缩激素 (MCH) 是黑皮质素信号传导的结果 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是否 由炎症刺激、脂多糖（LPS）注射诱导， 涉及与癌症厌食症相同的黑皮质素依赖性机制 通过使用与上述类似的实验策略。 通过提高我们对癌症厌食症机制的理解，这些 研究将有助于确定治疗的潜在中心目标 肥胖症以及厌食症治疗策略 慢性疾病状态。这项研究将为申请人做好准备 作为能源领域独立研究者的学术生涯 体内平衡。富人将促进向独立的过渡 Schwartz 博士和 Harborview 医疗中心提供的培训环境 能量代谢实验室，并通过加入一个富有生产力的大型社区 整个大学能量稳态领域的研究人员 华盛顿校区。