Regulation of cAMP - Dependent Protein Kinase Genes

cAMP 依赖性蛋白激酶基因的调节

• 批准号: 7885964
• 负责人: George STANLEY MCKNIGHT
• 金额: $ 41.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885964
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Adipose tissue; Back; Biological Assay; Body Weight; Brain; Brain region; Catalytic Domain; Chemicals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diet; Energy Metabolism; Fasting; Fatty acid glycerol esters; Feedback; Future; Genes; Genetic; Genetic Techniques; Genetic Transcription; Goals; Hormones; Hypersensitivity; Hypothalamic structure; JAK2 gene; Leptin; Leptin resistance; Messenger RNA; Molecular; Mus; Neurons; Obesity; Pathway interactions; Pattern; Phenotype; Physiological; Play; Polyribosomes; Population; Regulation; Regulatory Pathway; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; STAT3 gene; Signal Pathway; Signal Transduction; System; Techniques; Transgenic Organisms; Translating; Translational Regulation; Tyrosine Phosphorylation; Work; base; chemical genetics; clinical application; energy balance; feeding; human FRAP1 protein; in vivo; inhibitor/antagonist; leptin receptor; melanocortin receptor; mutant; neuroregulation; new therapeutic target; novel; prevent; public health relevance; recombinase; relating to nervous system; response; tool

DESCRIPTION (provided by applicant): One of the overall goals of this proposal is to understand the role of PKA signaling in the neuronal pathways that regulate feeding and energy expenditure. Mouse genetic techniques allow us to investigate this problem in a physiological setting and also provide us with novel tools for defining regulation at the molecular level. We propose to use a mouse genetic approach to detect and quantities neuron-specific mRNA regulation in regions of the hypothalamus known to be involved in body weight regulation and the response to the adipose derived hormone, leptin. In addition to detecting changes in transcription we will examine the potential role of translational control of pre-existing mRNAs. Recent work has continued to challenge and expand our views on the neural control of body weight. Leptin receptors have been shown to engage multiple signaling pathways in a neuron specific pattern and the crosstalk between these signaling systems, including the cAMP/PKA pathway, is a new avenue that needs to be explored more comprehensively. The RII2 KO mouse line is lean and resistant to diet-induced obesity and our recent results indicate that this is because of an increase in leptin sensitivity in the brain. The specific aims of this proposal are: (1) Identify the hypothalamic neurons in which PKA activity plays a role in leptin sensitivity and body weight regulation (2) Assay changes in polysome-associated mRNAs in specific hypothalamic neurons in response to diet and leptin (3) Determine the mechanism of increased leptin sensitivity in RII2 KO mice. The sensitivity of the hypothalamic response network to leptin is one of the ultimate determinants of how much energy is stored as fat and leptin resistance is one of the defining features of obesity. PUBLIC HEALTH RELEVANCE: The regulation of feeding and energy balance is coordinated by neurons in the hypothalamic region of the brain. We have demonstrated that intracellular signaling through the cAMP/Protein Kinase A system can regulate this neuronal pathway and prevent diet-induced obesity in mice. In this project, we will study this mechanism for regulating energy balance and hope to reveal novel therapeutic targets for future clinical applications.

描述（由申请人提供）：本提案的总体目标之一是了解PKA信号传导在调节进食和能量消耗的神经元通路中的作用。小鼠遗传技术使我们能够在生理环境中研究这个问题，也为我们提供了在分子水平上定义调控的新工具。我们建议使用小鼠遗传学方法来检测和定量已知参与体重调节和对脂肪源性激素瘦素的反应的下丘脑区域中的神经元特异性mRNA调节。除了检测转录的变化，我们还将研究预先存在的mRNA的翻译控制的潜在作用。最近的工作继续挑战和扩大我们对体重神经控制的看法。瘦素受体已被证明在神经元特异性模式中参与多个信号传导途径，并且这些信号传导系统（包括cAMP/PKA途径）之间的串扰是需要更全面地探索的新途径。RII 2 KO小鼠品系是瘦的并且抵抗饮食诱导的肥胖，并且我们最近的结果表明这是因为大脑中瘦素敏感性的增加。本研究的具体目的是：（1）鉴定PKA活性在瘦素敏感性和体重调节中起作用的下丘脑神经元;（2）分析特定下丘脑神经元中多聚体相关mRNA对饮食和瘦素的响应;（3）确定RII 2 KO小鼠瘦素敏感性增加的机制。下丘脑反应网络对瘦素的敏感性是多少能量以脂肪形式储存的最终决定因素之一，瘦素抵抗是肥胖的定义特征之一。 公共卫生相关性：进食和能量平衡的调节由大脑下丘脑区域的神经元协调。我们已经证明，通过cAMP/蛋白激酶A系统的细胞内信号传导可以调节这种神经元通路，并防止小鼠饮食诱导的肥胖。在这个项目中，我们将研究这种调节能量平衡的机制，并希望为未来的临床应用揭示新的治疗靶点。