Melanocortins, Energy Balance and Cancer Anorexia

描述（由申请人提供） 这个应用程序的目的是定义导致 在病理性厌食的情况下食欲下降和体重减轻。我们 以前的工作支持了肿瘤和其他炎症性疾病 刺激通过依赖于黑皮质素信号传导的机制引起厌食， 在生理条件下调节食物摄入的脑肽。信号 阐述了由肿瘤细胞提出的增加黑皮质素受体 信号，一个不适当的“饱足”信号，导致负能量 平衡，并导致无情的体重减轻。的效力 癌症通过黑皮质素系统对能量稳态的影响， 事实上，由体重减轻引起的补偿性变化，如减少 不能影响正常的下丘脑反应， 刺激恢复到基线体重。 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1）检测阿黑皮素原 弓状核（ARC）中的POMC是癌症的必要和充分条件。 厌食症的发生，同时使用基因敲除模型和腺病毒基因治疗 2）确定刺豚鼠相关肽是否通过信号传导 （Agrp），内源性黑皮质素拮抗剂，通过原位 杂交研究;和3）确定黑色素的下调是否 浓缩激素（MCH）是黑皮质素信号传导的结果， 介导厌食症，使用原位杂交以及腺病毒基因 治疗研究。第二个主要目标是调查厌食症是否 由炎性刺激、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机制 通过使用类似于上面概述的实验策略。 通过提高我们对癌症厌食症机制的理解， 研究将有助于确定治疗的潜在中心靶点， 肥胖以及治疗厌食症的特征策略， 慢性病状态。这项研究将为申请人准备一个 学术生涯作为一个独立的调查员在能源领域 体内平衡向独立的过渡将得到富人的推动 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社区的生产力 在整个大学的能量稳态领域的研究人员 华盛顿校园。

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.