STAT5 as an anti-obesity agent

肥胖症的流行在包括澳大利亚在内的第一世界国家是显而易见的。在这个国家，年龄在55-之间的男性中有27%患有肥胖症。肥胖会增加2型糖尿病、心血管疾病、肾脏疾病和子宫内膜癌等疾病的死亡率和发病率。鉴于我们疲软的生活方式，必须充分了解肥胖背后的代谢过程，以便开发合适的治疗方式。这项提议试图在我们理解肥胖的发展过程中建立一个重要的新元素，即转录因子STAT5。在之前NHMRC的支持下，我们开发了复杂的转基因小鼠，这种小鼠缺乏由抗肥胖剂生长激素启动的明确的信号传递过程。这些研究表明，激活STAT5的能力与抵抗肥胖之间存在很强的相关性。有零星的文献证据支持我们的假设，这也可以解释瘦素的一些抗肥胖作用。利用缺乏STAT5的小鼠，我们将确定STAT5作为抗肥胖剂的作用。澳大利亚人发现，STAT5的作用通常会被被称为SoCs的反馈抑制剂所阻断。我们将确定哪些SoCs是肥胖控制的反馈调节器，从而允许我们开发特定的抗SoCs药物，这些药物将作为新的抗肥胖剂发挥作用。

An obesity epidemic is evident in first world countries including Australia. Twenty seven percent of men aged 55-64 in this country are obese. Obesity results in increased mortality and morbidity from type 2 diabetes, cardiovascular disease, renal disease and endometrial cancer, among others. Given our flaccid lifestyles, it is imperative that the metabolic processes underlying obesity be fully understood, to allow development of suitable treatment modalities. This proposal seeks to establish an important new element in our understanding of the development of obesity, the transcription factor STAT5. With previous NHMRC support, we developed sophisticated genetically modified mice which lack defined signalling processes initiated by growth hormone, an anti-obesity agent. These studies showed a strong correlation between ability to activate STAT5 and resistance to obesity. There is fragmentary literature evidence to support our hypothesis, which could also explain some of leptins anti-obesity actions. Using mice which lack STAT5, we shall establish a role for STAT5 as an antiobesity agent. The actions of STAT5 are normally blocked by feedback inhibitors referred to as SOCS, discovered by Australians. We shall define which SOCS is the feedback regulator for obesity control, allowing us to develop specific anti-SOCS agents which will act as novel anti-obesity agents.