The control of growth and metabolism by effectors of the TOR signaling pathway
TOR 信号通路效应子对生长和代谢的控制
基本信息
- 批准号:7304845
- 负责人:
- 金额:$ 20.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-09 至 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsAutophagocytosisBenignBindingBiological AssayBiological ModelsBiological ProcessCancer EtiologyCatabolic ProcessCellsComplexConditionConsumptionDataDefectDeveloped CountriesDevelopmentDiabetes MellitusDigestionDiseaseDrosophila genusEnergy MetabolismFamilyFamily memberFat BodyFatty AcidsFatty LiverFatty acid glycerol estersGeneticGlucoseGrowthHumanInsulinInsulin ResistanceKnowledgeLigandsLinkLipidsLipodystrophyLiverLongevityMammalsMeasuresMediatingMediator of activation proteinMetabolicMetabolic ControlMetabolismMusNon-Insulin-Dependent Diabetes MellitusNuclear Hormone ReceptorsNuclear ReceptorsNutrientNutritionalObesityOrthologous GenePathway interactionsPhenotypePhosphotransferasesProcessProtein BiosynthesisProteinsPublic HealthRegulatory PathwayResearchRoleSignal PathwaySignal TransductionSignaling MoleculeStarvationSteroidsSystemTestingTimeTissuesTriglyceridesTuberous SclerosisUnited Statescell growthdetection of nutrientgenetic manipulationimprovedinsulin signalinglipid biosynthesislipid metabolismlipinemembermutantobesity treatmentreceptorreceptor functionresponsesensorsteroid hormonetumor
项目摘要
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.
描述(申请人提供):生长和新陈代谢与营养供应密切相关。协调这些过程的一个关键调控途径是营养敏感的TOR途径。通过TOR激酶的信号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,自噬是细胞在饥饿条件下通过“自我消化”来调动营养物质的过程。TOR受营养物质和胰岛素信号的控制,因此将这些输入整合到一个更广泛的控制新陈代谢的调节网络中。TOR途径的异常与癌症、良性肿瘤(结节性硬化症)有关,并与糖尿病和肥胖症有关。然而,介导TOR对糖脂代谢影响的下游效应因子在很大程度上尚不清楚。最近,在代谢控制中起作用的核激素受体已经成为有希望的候选者。该项目旨在弥合我们对TOR功能下游调节剂的了解差距。它将通过(1)研究进化上保守的脂代谢和肥胖的关键调节因子(Lipin)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)研究果蝇脂(DLipin)与TOR信号在生长控制中的相互作用。这将包括分析代谢参数(甘油三酯、葡萄糖、能量消耗等)。在不同的营养条件下,缺乏这两种蛋白质中的一种或两种。(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,表明它在这一重要过程的控制中与TOR合作。这一假说将通过分析动物的自噬标记来验证,在这些动物中,dLipin的活性或TOR和dLipin的活性都通过基因操作发生了变化。(3)确定核受体与dLipin在代谢和生长控制中的协同作用。初步数据表明,dLipin类似于哺乳动物的Lipin1,可被类固醇激素诱导。此外,最近研究表明,Lipin1的功能至少部分是通过作为核受体的协同调节来实现的。功能相关的dLipin-受体相互作用将使用为描述果蝇核受体的特征而开发的‘配体传感器’系统来识别。因此,该项目将为更好地理解TOR和类固醇信号通路如何相互连接铺平道路。在美国和其他工业化国家,肥胖和糖尿病已经成为公共卫生的主要挑战。该项目将研究脂肪代谢和肥胖的关键调节因子如何与营养和胰岛素敏感的TOR信号通路合作。因此,它将提高我们对营养感知如何与脂肪代谢联系在一起的理解,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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Roles of the FOXA transcription factor Fork head in autophagic developmental cell death.
FOXA 转录因子叉头在自噬发育细胞死亡中的作用。
- DOI:10.4161/auto.6335
- 发表时间:2008
- 期刊:
- 影响因子:13.3
- 作者:Lehmann,Michael
- 通讯作者:Lehmann,Michael
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MICHAEL LEHMANN其他文献
MICHAEL LEHMANN的其他文献
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{{ truncateString('MICHAEL LEHMANN', 18)}}的其他基金
A Genetic Model of NMDA Receptor Function in Cell Death
细胞死亡中 NMDA 受体功能的遗传模型
- 批准号:
8433815 - 财政年份:2013
- 资助金额:
$ 20.43万 - 项目类别:
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