The control of growth and metabolism by effectors of the TOR signaling pathway

描述（由申请人提供）：生长和代谢与营养物质的可用性密切相关。协调这些过程的关键调节途径是营养敏感性TOR途径。通过TOR激酶的信号传导通过细胞代谢的复杂变化促进细胞生长，包括刺激一般蛋白质合成。与此同时，TOR增加脂肪储存并阻止自噬，这是一种“自我消化”过程，细胞在饥饿条件下动员营养。TOR受营养素和胰岛素信号的控制，因此将这些输入整合到控制代谢的更广泛的调节网络中。TOR通路的失调与癌症有关，导致良性肿瘤（结节性硬化症），并与糖尿病和肥胖有关。然而，介导TOR对葡萄糖和脂质代谢的影响的下游效应物在很大程度上是未知的。最近，在代谢控制中起作用的核激素受体已成为有希望的候选者。该项目旨在填补我们对TOR功能下游介质的知识空白。它将通过（1）研究脂质代谢和肥胖（Lipin）的进化保守的关键调节因子整合到TOR信号通路中，以及（2）分析Lipin与核受体的功能相互作用来实现这一点。该项目将使用遗传模式生物果蝇，它在过去为我们理解包括人类在内的哺乳动物中的TOR信号做出了重要贡献。该项目的具体目标是： (1)研究果蝇Lipin（dLipin）与TOR信号在生长调控中的相互作用。这将包括测定代谢参数（甘油三酯、葡萄糖、能量消耗等）。在不同的营养条件下，在缺乏两种蛋白质中的一种或两种的动物中。(2)研究dLipin在自噬中的作用。初步数据显示，dLipin在自噬过程中强烈上调，表明它与TOR合作控制这一重要过程。该假设将通过分析动物中的自噬标志物来检验，其中dLipin或TOR和dLipin两者的活性通过遗传操作而改变。(3)鉴定与dLipin协同调控代谢和生长的核受体。初步数据表明，dLipin，类似于哺乳动物Lipin1，是由类固醇激素诱导。此外，Lipin1最近已被证明至少部分地通过充当核受体辅助调节剂来发挥作用。dLipin受体相互作用的功能相关性将被确定使用的'配体传感器'系统开发的核受体在果蝇的表征。因此，该项目将为更好地了解TOR和类固醇信号通路如何相互联系铺平道路。肥胖症和糖尿病已经成为美国和其他工业化国家公共卫生的主要挑战。该项目将研究脂质代谢和肥胖的关键调节因子如何与营养和胰岛素敏感性TOR信号通路合作。因此，它将提高我们对营养感测如何与脂肪代谢相关联的理解，并有助于为肥胖相关（2型）糖尿病和其他疾病的治疗铺平道路。

DESCRIPTION (provided by applicant): Growth and metabolism are closely linked to nutrient availability. A key regulatory pathway that coordinates these processes is the nutrient-sensitive TOR pathway. Signaling through the TOR kinase promotes cellular growth through complex changes in cell metabolism, including a stimulation of general protein synthesis. At the same time, TOR increases fat stores and blocks autophagy, a process of 'self-digestion' by which cells mobilize nutrients under starvation conditions. TOR is controlled by both nutrients and insulin signaling, and thus integrates these inputs into a broader regulatory network that controls metabolism. Dysreglulation of the TOR pathway is associated with cancers, causes benign tumors (tuberous sclerosis), and has been linked to diabetes and obesity. However, the downstream effectors that mediate the effects of TOR on glucose and lipid metabolism are largely unknown. Recently, nuclear hormone receptors that function in metabolic control have emerged as promising candidates. This project aims at closing gaps in our knowledge of downstream mediators of TOR function. It will do this by (1) studying the integration of an evolutionarily conserved key regulator of lipid metabolism and obesity (Lipin) into the TOR signaling pathway, and (2) analyzing the functional interaction of Lipin with nuclear receptors. The project will use the genetic model organism Drosophila, which has made important contributions in the past to our understanding of TOR signaling in mammals including humans. The specific aims of the project are: (1) To characterize the interaction between Drosophila Lipin (dLipin) and TOR signaling in growth control. This will include assaying metabolic parameters (triglycerides, glucose, energy consumption etc.) under different nutritional conditions in animals lacking one or both of the two proteins. (2) To characterize the function of dLipin in autophagy. Preliminary data show that dLipin is strongly upregulated during autophagy, suggesting that it cooperates with TOR in the control of this important process. This hypothesis will be tested by analyzing markers of autophagy in animals in which the activities of dLipin, or both TOR and dLipin, were changed by genetic manipulation. (3) To identify nuclear receptors cooperating with dLipin in metabolic and growth control. Preliminary data suggest that dLipin, similar to mammalian Lipin1, is inducible by steroid hormone. In addition, Lipin1 has recently been shown to function, as least in part, by acting as a nuclear receptor co-regulator. dLipin-receptor interactions of functional relevance will be identified using a 'ligand sensor' system developed for the characterization of nuclear receptors in Drosophila. The project will thus pave the way for a better understanding of how TOR and steroid signaling pathways are interconnected. Obesity and diabetes have become a major challenge to public health in the United States and other industrialized nations. This project will examine how a key regulator of lipid metabolism and obesity cooperates with the nutrient and insulin-sensitive TOR signaling pathway. It will thus improve our under- standing of how nutrient sensing is linked to fat metabolism and help paving the way for treatments of obesity-related (type 2) diabetes and other diseases.