Regulation of cAMP - Dependent Protein Kinase Genes

描述(由申请人提供)：本提案的总体目标之一是了解PKA信号在调节摄食和能量消耗的神经通路中的作用。小鼠基因技术使我们能够在生理环境中研究这个问题，也为我们在分子水平上定义调控提供了新的工具。我们建议使用小鼠遗传学方法来检测和定量下丘脑中已知的与体重调节和对脂肪衍生激素瘦素的反应有关的神经元特异性mRNA调节。除了检测转录的变化外，我们还将研究预先存在的mRNAs的翻译控制的潜在作用。最近的工作继续挑战和扩大了我们对体重神经控制的看法。瘦素受体以神经元特有的模式参与多个信号通路，这些信号系统之间的串扰，包括cAMP/PKA通路，是一个需要更全面地探索的新途径。RII2KO小鼠是瘦小的，对饮食诱导的肥胖具有抵抗力，我们最近的结果表明，这是由于大脑中瘦素敏感性的增加。该建议的具体目的是：(1)确定在瘦素敏感性和体重调节中发挥作用的下丘脑神经元(2)检测特定下丘脑神经元中多聚体相关mRNAs对饮食和瘦素的反应变化(3)确定RII2 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最终决定能量储存为脂肪的因素之一，而瘦素抵抗是肥胖的定义特征之一。 与公共健康相关：摄食和能量平衡的调节由大脑下丘脑区的神经元协调。我们已经证明，通过cAMP/蛋白激酶A系统的细胞内信号可以调节这一神经通路，并防止饮食诱导的小鼠肥胖。在本项目中，我们将研究这一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。

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.