恶液质（cachexia）是肿瘤常见并发症，其发展加重是多数肿瘤治疗失败的重要原因。已知下丘脑相关神经元功能异常,可致厌食和分解代谢亢进，是恶液质形成的重要环节。弓状核POMC神经环路是下丘脑厌食中枢的核心部分，受Stat3信号调控，其过度激活，可致厌食和机体分解代谢加剧。我们的前期研究发现，肿瘤恶液质动物下丘脑Stat3通路明显激活，但原因不清。磷脂鞘氨醇(S1P)是体内的一种脂代谢产物，在肿瘤患者中急剧增加，并诱导肿瘤细胞Stat3持续激活，是肿瘤预后不良的重要机制。我们推测，下丘脑S1P-Stat3轴病理性激活，参与了肿瘤恶液质的形成。本课题拟研究S1P对下丘脑POMC神经元Stat3活化的影响，阐述S1P-Stat3轴在恶液质形成中的作用，探讨以S1P为靶点进行恶液质治疗的可行性。本课题结果将阐明肿瘤相关因子S1P对下丘脑及能量代谢紊乱的影响，为恶液质的防治提供新的思路。

Cancer cachexia is a complex syndrome of progressive weight loss especially devastating to skeletal muscle and adipose tissue, normally liked with high motility. The clinical characterization of cancer cachexia includes a number of signs and symptoms interfering with the imbalance energy intake and energy expenditure. Recent study demonstrated that the abnormal activation of POMC neuron in hypothalamus and the release of alpha-MSH play a key role for the development of cachexia, the aberrant activation of POMC neuron directly reduced appetite and increased metabolic rate, which cause the energy imbalance. In our recent study, we found that，in cancer cachexia mouse model, the constitutively activation of Stat3 in POMC neuron seems to be the pathological feature of cachexia, which directly control the activation of POMC and the release of alpha-MSH, however, the molecular mechanism is not clear. Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that has been shown to regulate cell growth, cell survival, cell invasion, vascular maturation, and angiogenesis, processes that are important for cancer progression, however, its function in hypothalamus and cachexia development is never known. Some clinical study has demonstrated that increased production of S1P in cancer patients, here in this study, we hypothesis that S1P regulated aberrant Stat3 activation in hypothalamus might directly control the peripheral metabolic status, control the development of cachexia. To address this question, we are going to investigate: 1) the influence of S1P to Stat3 activation in hypothalamus and the involved molecular mechanism; 2) the therapeutic effect of S1P signaling inhibitor FTY720 in cancer cachexia by using the relevant disease mouse model; This study will provide direct experimental evidence to test the possibility for the treatment of cancer cachexia by targeting S1P/Stat3 in hypothalamus.